Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea.[3][11] It is sometimes prescribed off-label for treating Attention deficit hyperactivity disorder (ADHD) in children, having no benefit in ADHD for most adults.[12] While it has seen off-label use as a purported cognitive enhancer to improve wakefulness, in animal and human studies the research on its effectiveness for this use is inconclusive.[13][14] Modafinil is taken by mouth.[3] It comes in oral tablet form of 100mg or 200mg. Clinical studies have not found evidence of diminished response or tolerance to modafinil's wakefulness-promoting properties at therapeutic doses over prolonged periods. In addition to its medical uses, modafinil has gained popularity among students, office workers, professionals, and others who seek enhanced wakefulness and cognitive function.[15] However, studies have shown mixed results regarding its cognitive enhancement abilities.[12]

Clinical data
Trade namesProvigil, Alertec, Modavigil, others
Other namesCRL-40476; Diphenylmethyl-sulfinylacetamide
License data
  • AU: D
Relatively low
Very low to low[1][2]
Routes of
By mouth[3]
Drug classCNS stimulant
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNot determined due to its aqueous insolubility
Protein binding62.3%
MetabolismLiver (primarily via amide hydrolysis);[7] CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved[10]
Elimination half-life12-15 hours[7] (modafinil, the racemic mixture),
15 hours (armodafinil, the (R)-enantiomer),[8]
4 hours (esmodafinil, the (S)-enantiomer).[9]
ExcretionUrine (80%)
  • 2-(diphenylmethanesulfinyl)acetamide
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.168.719 Edit this at Wikidata
Chemical and physical data
Molar mass273.35 g·mol−1
3D model (JSmol)
  • O=S(C(c1ccccc1)c2ccccc2)CC(=O)N
  • InChI=1S/C15H15NO2S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H2,16,17) checkY

While modafinil is generally well-tolerated when used according to proper dosing guidelines, it does carry potential risks and side effects that should be considered before use. Additionally, there are concerns about the potential abuse of modafinil due to its stimulant-like properties. Modafinil's side effects include headaches, anxiety, and nausea. Serious side effects in high doses include delusions, unfounded beliefs, paranoia, irrational thought, and transient depression, possibly due to its effects on dopamine receptors in the brain, as well as allergic reactions. The amount of medication used should be adjusted in those with kidney problems, as this medication has markedly increased side effects during renal insufficiency.[16] It is not recommended in those with an arrhythmia, significant hypertension, or left ventricular hypertrophy.[16] Modafinil appears to work by acting on dopamine and modulating the areas of the brain involved with the sleep cycle.[3]

Originally developed in the 1970s by French neuroscientist Michel Jouvet and Lafon Laboratories, Modafinil has been prescribed in France since 1994,[17] and was approved for medical use in the United States in 1998.[11] Its legal status varies by jurisdiction; in the United States it is classified as a schedule IV controlled substance,[6] whereas in the United Kingdom it is a prescription only medication.[16] In some countries no controls apply. It is available as a generic medication.[16] In 2020, modafinil was the 302nd most commonly prescribed medication in the United States, with just over 1000000 prescriptions.[18] There are ongoing debates around using modafinil as a performance-enhancing drug or "smart drug", especially outside of medically approved uses like treating sleep disorders or ADHD. Some view its usage negatively due to ethical concerns about unfair advantages or reliance on drugs for improved productivity.[12]

Usage edit

Medical edit

Due to modafinil's lack of euphoric effects, it is not considered to be a classical psychostimulant, but rather is classified as a eugeroic (wakefulness-promoting drug).[3]

Sleep disorders edit

Modafinil is used primarily for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.[11][13][19][20] For obstructive sleep apnea, it is recommended that patients use continuous positive airway pressure (CPAP) appropriately before they consider starting modafinil to help with daytime sleepiness.[3] Because of the risk of development of skin or hypersensitivity reactions and serious adverse psychiatric reactions, the European Medicines Agency recommended that new patient prescriptions should be only to treat sleepiness associated with narcolepsy.[21]

Multiple sclerosis-related fatigue edit

The UK National Institute for Health and Care Excellence (NICE) and MS NGOs suggest modafinil to help with multiple sclerosis (MS) fatigue[22][23][24] off-label.[12] Still, the results from two controlled studies are conflicting, given the lack of larger, long-term, randomized controlled studies.[25]

Attention deficit hyperactivity disorder edit

Modafinil is sometimes prescribed off-label to people with attention deficit hyperactivity disorder (ADHD).[26][27][28] However, there is a lack of research into modafinil for ADHD and, consequently, evidence supporting its use in adult ADHD compared to other treatments such as lisdexamfetamine.[29][30]

Bipolar depression edit

A 2020 meta-analysis found that "augmentation with [modafinil or armodafinil] was associated with significantly greater rates of treatment response" in patients with bipolar depression "with no evidence of increased risk of mood switch or suicide attempts".[31]

Occupational edit

Modafinil was fielded to military personnel in the French Air Force, Foreign Legion, and Marine infantry during the Gulf War.

Adrafinil, a prodrug of modafinil, was first offered as an experimental treatment for narcolepsy in France in 1986.[17] Modafinil, being more efficient than adrafinil, was deemed combat-worthy by the French Ministry of Defense in 1989 and was subsequently administered to personnel by their officers under the name Virgyl. This was done to improve a unit's "operational tempo", which refers to the rate at which military operations or activities are conducted. The goal was to enhance the unit's overall performance and efficiency. This evaluation took place before the introduction of modafinil on the market as medication in 1994,[17] and the personnel involved were not informed of the product's nature.[32] Later studies did not confirm the benefit of modafinil in military contexts that do not involve sleep deprivation.[33]

Since then, armed forces of several countries, including the United States, the United Kingdom, India, and France, have expressed interest in modafinil as an alternative to amphetamine—the drug traditionally employed in combat situations or lengthy missions in which troops face sleep deprivation. The French government indicated that the Foreign Legion used modafinil during certain covert operations.[34] The United Kingdom's Ministry of Defence commissioned research into modafinil[35] from QinetiQ and spent £300,000 on one investigation.[36] In 2011, the Indian Air Force announced that modafinil was included in contingency plans.[37]

In the United States military, modafinil has been approved for use on certain Air Force missions, and it was investigated for other military uses.[38] In 2012, modafinil was the only drug approved by the Air Force as a "go pill" for fatigue management (replacing prior use of amphetamine-based medications such as dextroamphetamine).[39]

The Canadian Medical Association Journal 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.[40]

The use of modafinil in military contexts that do not involve sleep deprivation is not recommended due to limited evidence on its effectiveness as a cognitive enhancer for non-sleep-deprived individuals. Additionally, there are potential risks of abuse, overconfidence, and negative impact on physical performance associated with modafinil use outside the context of sleep deprivation.[33]

Non-medical edit

Modafinil has been used non-medically as a "smart drug" by students,[41] office workers, transhumanists,[42] professionals in the corporate and tech fields,[15] surgeons, truck drivers, and call-center workers.[43][44][45] Its attention-promoting, cognitive-enhancing, and wakefulness-boosting properties are cited by those people as reasons behind modafinil's use.[46][47] However, multiple studies have consistently shown that modafinil does not provide cognitive enhancement or attention improvement benefits in non-sleep-deprived individuals, with some studies even reporting impairments in certain cognitive functions.[48]

Available forms edit

Modafinil tablets – Modalert 200

Modafinil is available as 100 and 200 mg oral tablets.[11] It is also available as the (R)-enantiomer, armodafinil, and as a prodrug of modafinil, adrafinil.[49]

Drug tolerance edit

Large-scale clinical studies have not found evidence of diminished response (drug tolerance) to modafinil's pro-wakefulness and anti-fatiguing properties at therapeutic doses over periods as long as three years.[50][51][52]

Contraindications edit

Modafinil is contraindicated in people with known hypersensitivity to modafinil or armodafinil.[53] Modafinil is not approved for use in children for any medical conditions, in whom there is a higher risk of rare but serious dermatological toxicity.[54][55][56]

Due to limited available information on the excretion of modafinil into breastmilk and its potential effects on infants, careful monitoring of the infant is recommended when breastfeeding mothers use modafinil or considering alternative drugs may be preferred until more safety data are available.[57]

Adverse effects edit

The incidence of adverse effects are reported as the following: less than 10% of users report having a headache, nausea, and decreased appetite. Between 5% and 10% of users may be affected with anxiety, insomnia, dizziness, diarrhea, and rhinitis.[12] Modafinil-associated psychiatric reactions have occurred in those with and without a preexisting psychiatric history.[58] No clinically significant changes in body weight have been observed with modafinil in clinical trials,[59] although decreased appetite and weight loss have been reported with modafinil in children and adolescents probably due to the much higher modafinil exposure in these individuals based on body weight (i.e., mg/kg doses).[60]

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 surveillance experiences[61] which means adverse effects or reactions that have been reported after the drug was approved and made available on the market, indicating incidents that occurred in real-world use rather than just clinical trials.[62]

In 2007, the FDA ordered Cephalon to modify the Provigil leaflet to add in bold-face print 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.[63] However, a longitudinal study in pediatric patients treated for narcolepsy for up to ten years demonstrated that modafinil and armodafinil were safe and effective, with the study concluding that use of modafinil and armodafinil significantly improved patients' ability to stay awake and did not exacerbate preexisting psychiatric conditions.[64]

Addiction and dependence edit

The addiction and dependence liabilities of modafinil are very low.[1][65] Modafinil shares biochemical mechanisms with addictive stimulant drugs, and some studies reported it to have similar mood-elevating properties, although to a lesser degree.[65] It is not clear whether these effects are different from those from caffeine.[66][67] Modafinil does not appear to produce euphoric effects nor deviations (i.e., abuse) from dosages assigned to the patient.[68] Still, caution should be taken, because in clinical trials modafinil produced euphoric and psychoactive effects, altering thinking, mood, feelings, and perception like other CNS stimulants,[12] so the risk of potential abuse still has to be assessed,[12] the risk of potential abuse, as there are indications that modafinil may work on the same neurobiological mechanisms as other addictive stimulants.[33]

Modafinil is classified by the United States Drug Enforcement Administration as a schedule IV controlled substance,[6] a category for drugs with valid medical uses and low addiction potential.[1][69] The International Narcotics Control Board does not consider modafinil a narcotic[70] nor a psychotropic substance.[71] Modafinil may increase abstinence rates in a subgroup of cocaine addicts, and modafinil-related discontinuation adverse effects are no different from placebo.[72]

Overdose edit

In mice and rats, the median lethal dose (LD50) of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values for rats range from 1000 to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. Clinical trials on humans involve taking up to 1200 mg/day for 7–21 days. 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.[11] In 2005, the FDA was not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs including modafinil).[11]

Interactions edit

Modafinil is a weak to moderate inducer of CYP3A4[73][74] and a weak inhibitor of CYP2C19, enzymes of the cytochrome P450 group of enzymes.[12] Modafinil also induces or inhibits other cytochrome P450 enzymes. One in vitro study predicts that modafinil may induce the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as may inhibit CYP2C9 and CYP2C19.[10] However, other in-vitro studies find no significant inhibition of CYP2C9.[7][75] Modafinil may induce P-glycoprotein, which may affect drugs transported by P-glycoprotein, such as digoxin.[76] Therefore, modafinil affects pharmacodynamics of drugs which are metabolized by CYP3A4 and other enzymes of the cytochrome P450 family.[73]

For instance, induction of CYP3A4 by modafinil affects metabolism of the following medications and endogenous substances:[77]

  • opioids, such as methadone, hydrocodone, oxycodone, or fentanyl - modafinil may result in a drop in opioid plasma concentrations because of faster clearance by CYP3A4. If the patient is not monitored closely, reduced efficacy or withdrawal symptoms can occur.[77]
  • steroid hormones, such as estradiol, progesterone or cortisol. Modafinil may have an adverse effect on hormonal contraceptives for up to a month after discontinuation.[78] In a 2006 study, a single dose of modafinil 200 mg caused a decrease in blood prolactin levels, although it did not affect human growth hormone or thyroid-stimulating hormone.[79][80] Since modafinil induces the activity of the CYP3A4 enzyme involved in cortisol clearance,[81] modafinil may reduce the bioavailability of hydrocortisone. Therefore, it may be necessary to adjust the steroid substitution dose in subjects receiving CYP3A4-metabolism-inducing drugs such as modafinil.[82]

Pharmacology edit

Pharmacodynamics edit

Modafinil activity profile
Site Potency Type Species Refs
DATTooltip Dopamine transporter 1.8–2.6 μM
4.8 μM
6.4 μM
4.0 μM
NETTooltip Norepinephrine transporter >10 μM
>92 μM
35.6 μM
136 μM
SERTTooltip Serotonin transporter >10 μM
46.6 μM
>500 μM
>50 μM
D2 >10 μM
16 nMb
120 nMb
Footnotes: a = Functional activity, not binding inhibition. b = Armodafinil at D2High. Notes: No activity at a variety of other assessed targets.[83]

Mechanism of action edit

The precise therapeutic mechanism of action of modafinil for narcolepsy[88] and sleep-wake disorders remains unknown,[89][90] however, the effect seems to be caused by binding of modafinil to the dopamine transporter and inhibiting dopamine reuptake.[88] Modafinil acts as an atypical, selective, and weak dopamine reuptake inhibitor and indirectly activates the release of orexin neuropeptides and histamine from the lateral hypothalamus and tuberomammillary nucleus, all of which may contribute to heightened arousal.[89][90][91][92]

Dopamine reuptake inhibitor edit

Modafinil elevates dopamine levels in the hypothalamus in animals.[93] The locus of the monoamine action of modafinil was also studied, with effects identified on dopamine in the striatum and, in particular, nucleus accumbens,[94][95] norepinephrine in the hypothalamus and ventrolateral preoptic nucleus,[96][97] and serotonin in the amygdala and frontal cortex.[98] Modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology.[83] Of the sites tested, it was observed to significantly affect only the dopamine transporter (DAT), acting as a dopamine reuptake inhibitor (DRI) with an IC50 value of 4 μM.[83] Modafinil binds to the same site on the DAT as cocaine, but in a different manner.[99][100] Modafinil increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine (GBR-12909),[101] 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".[102] In addition to animal research, a human positron emission tomography (PET) imaging study observed that 200 mg and 300 mg doses of modafinil resulted in DAT occupancy of 51.4% and 56.9%, respectively, which is "close to that of methylphenidate".[103] Another human PET imaging study similarly observed that modafinil occupied the DAT and also determined that it significantly elevated extracellular levels of dopamine in the brain, including in the nucleus accumbens.[104]

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.[105][106] For instance, modafinil produces wakefulness reportedly without the need for compensatory sleep, and shows relatively low, if any, potential for abuse.[107][102][105][106] Aside from modafinil, other atypical DAT inhibitors include vanoxerine and benztropine, which have a relatively low abuse potential similar to modafinil.[105] These drugs appear to interact with the DAT in a distinct way from "conventional" DAT blockers such as cocaine and methylphenidate.[100][105] Analogues of modafinil with modafinil-like versus cocaine-like dopamine reuptake inhibition and effects have been synthesized.[108]

Dopamine transporter-independent actions edit

Evidence against the hypothesis that modafinil exerts its effects by acting as a DRI is that tyrosine hydroxylase inhibitors (which deplete dopamine) fail to block the effects of modafinil in animals.[109] Modafinil fails to reverse reserpine-induced akinesia, whereas dextroamphetamine, a dopamine releasing agent (DRA), is able to do so.[110] One of the first published structure–activity relationship studies of modafinil found that DAT inhibition did not correlate with wakefulness-promoting effects in animals among modafinil analogues.[111] A variety of analogues without significant DAT inhibition still produce wakefulness-promoting effects.[111] "[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".[107] Another 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.[93] Taken together, although it is established that modafinil is a clinically significant DRI, its full pharmacology remains unclear, and may include DAT-independent actions.[99][107] One such action may be activation of the orexin system.[92][99][107]

There is nonetheless evidence that modafinil produces at least some of its wakefulness-promoting effects by acting as a DRI, or at least via activation of the dopaminergic system. In support of the hypothesis that modafinil acts as a dopaminergic agent, its wakefulness-promoting effects are abolished in DAT knockout mice (although DAT knockout mice show D1 and D2 receptor and norepinephrine compensatory abnormalities that might confound this finding), reduced by both D1 and D2 receptor antagonists (although conflicting reports exist),[110] and completely blocked by simultaneous inactivation of both D1 and D2 receptors.[102] Modafinil shows full stimulus generalization (ability to produce similar effects or responses) to other DAT inhibitors including cocaine, methylphenidate, and vanoxerine, and discrimination (ability to differentiate or distinguish between different drugs) is blocked by administration of both ecopipam (SCH-39166), a D1 receptor antagonist, and haloperidol, a D2 receptor antagonist.[106] Partial substitution (a phenomenon where a substance or drug partially replaces or mimics the effects of another substance or drug) 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).[106]

Modafinil may have 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.[112] However, modafinil sulfone lacks wakefulness-promoting effects in animals, indicating that a distinct mechanism may be at play in the anticonvulsant effects of both compounds.[112]

Dopamine D2 receptor partial agonist edit

Armodafinil, the (R)-enantiomer of modafinil, acts as a D2High receptor partial agonist,[113] with a Ki of 16 nM, an intrinsic activity of 48%, and an EC50 of 120 nM, in rat striatal tissue.[87] Esmodafinil, the (S)-enantiomer of modafinil, is inactive with respect to the D2 receptor.[87] Modafinil directly inhibits the firing of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra of rats via activation of D2 receptors.[114] However, modafinil seems not to interact with the human D2 receptor (Ki = >10 μM).[83]

Dampening of amygdala activity edit

There is some mouse and human evidence (via direct fMRI observation and anxiety questionnaires) to suggest that modafinil may reduce amygdala activity.[115][116] The amygdala is involved in fear processing, and the dampening of its activity reduces perceptions of fear in response to environmental stress.[117] One study documented a statistically significant reduction in fear response among human subjects given 100 mg of modafinil daily for 7 days.[115] However, another study investigating the acute effects of modafinil on fear processing reported an increase in amygdala responses to fearful faces after administration of 600 mg of modafinil in human subjects.[118] Modafinil's dose dependent effects on fear processing may exhibit a Yerkes–Dodson relationship.[119]

Pharmacokinetics edit

Cmax (peak levels) occurs approximately 2 to 3 hours after modafanil administration. Food slows absorption of modafanil, but does not affect the total AUC. In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage changes very little when the concentration of modafinil is varied.[120]

Renal excretion of unchanged modafinil usually accounts for less than 10% of an oral dose. This means that when modafinil is taken by mouth, less than 10% of the drug is eliminated from the body through the urine without being metabolized (broken down) by the liver or other organs. The rest of the drug is either metabolized or excreted through other routes, such as feces or bile.[7] The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056).[121] Both of these metabolites have been described as inactive,[122] and neither appears to contribute to the wakefulness-promoting effects of modafinil.[121][7][123] However, modafinil sulfone does appear to possess anticonvulsant effects, a property that it shares with modafinil.[112]

Elimination half-life is in the range of 10 to 12 hours, subject to differences in cytochrome P450 genotypes, liver function, and renal function. Modafinil is metabolized mainly in the liver,[7] and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug is usually less than 10%, but can range from 0% to as high as 18.7%, depending on the factors mentioned.[120]

Chemistry edit

Enantiomers edit

Armodafinil ((R)-(−)-modafinil)
Esmodafinil ((S)-(+)-modafinil)

Modafinil is a racemic mixture of two enantiomers, armodafinil ((R)-modafinil) and esmodafinil ((S)-modafinil).[86][124]

Detection in body fluids edit

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.[125][126] In 2011, modafinil was not 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.[86]

Reagent testing can screen for the presence of modafinil in samples.[127][128]

Colors produced by modafinil with various reagents
RC Marquis Reagent Liebermann Froehde
Modafinil Yellow/Orange > Brown[127][128] Darkening Orange[127] Deep orange/red[128]

Structural analogues edit

Many derivatives and structural analogues of modafinil have been synthesized and studied.[108][129][100] Examples include adrafinil, CE-123, fladrafinil (CRL-40941; fluorafinil), flmodafinil (CRL-40940; bisfluoromodafinil, lauflumide), and modafinil sulfone (CRL-41056).[130]

History edit

Modafinil was originally developed in France by Neurophysiology professor Michel Jouvet and Lafon Laboratories. Modafinil was among a series of benzhydryl sulfinyl compounds invented in the 1970s, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986.[17] Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,[131] and has similar activity to the parent drug. Modafinil has been prescribed in France since 1994 under the name Modiodal,[17] and in the US since 1998 as Provigil. In contrast, adrafinil does not have FDA approval, and it was marketed in France until 2011 and then withdrawn.[132]

In 1998, modafinil was approved by the US Food and Drug Administration[6][133] for the treatment of narcolepsy and in 2003, for shift work sleep disorder and obstructive sleep apnea/hypopnea[134] even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.[90]

Modafinil was approved for use in the UK in December 2002. Modafinil is marketed in the United States by Cephalon,[135] who originally leased the rights from Lafon, but eventually purchased the company in 2001.[135]

Cephalon began to market armodafinil, the (R)-enantiomer of modafinil, in the United States in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the US in 2012.[136][137]

Patent protection and litigation edit

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, the patent expired on October 22, 2010.[138]

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. It was reissued in 2002 as RE 37,516, which surrendered the 5618845 patent. With pediatric exclusivity, this patent expired on April 6, 2015.[139][140]

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.[141] At least one withdrew its application after early opposition by Cephalon based on the RE 37,516 patent. There is uncertainty about whether a particle size patent is sufficient protection against the manufacture of generics: including 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" of this sort are required.[142]

On October 31, 2011, US Reissue Patent No. RE 37,516 was declared invalid and unenforceable.[143] 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.[144] The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.[144]

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.[145][146]

This agreement was challenged by a class of wholesalers who bought Provigil directly from Cephalon, who claimed that Cephalon and the generic manufacturers conspired to keep the modafinil price artificially high and violated antitrust laws. The plaintiffs brought a case to the United States District Court for the Eastern District of Pennsylvania in 2006. They alleged that Cephalon, the patent holder of Provigil, and four generic drug manufacturers (Teva, Ranbaxy, Mylan, and Barr) entered into unlawful reverse payment settlements that delayed the entry of generic modafinil into the market and maintained Cephalon's monopoly. The plaintiffs claimed that they paid artificially inflated prices for Provigil due to the anticompetitive agreements. The plaintiffs sought damages and injunctive relief under the Sherman Act and various state laws. The district court dismissed the plaintiffs' claims in 2015, finding that they failed to allege that the settlements were anticompetitive plausibly. The court applied the rule of reason analysis, which weighs the procompetitive and anticompetitive effects of an agreement, and concluded that the plaintiffs did not show that the generic manufacturers would have entered the market earlier absent the settlements or that the patent was invalid or not infringed. The court also found that the settlements had some procompetitive benefits, such as allowing early entry of generic modafinil before the patent expired and providing compensation to consumers. The plaintiffs appealed to the Third Circuit Court of Appeals, which affirmed the district court's decision in 2016. Therefore, the court concluded that the settlements did not violate antitrust laws.[147]

Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals.[148][149] Cephalon sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil).[150] 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;[151] ultimately, Par Pharmaceutical acquired the US modafinil rights as well as some others.[152]

In the United Kingdom, Mylan Inc. received regulatory approval to sell generic modafinil produced by Orchid in January 2010; Cephalon sued to prevent sale, but lost the patent trial.[153]

Society and culture edit

Legal status edit

Australia edit

In Australia, modafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy.[154] Schedule 4 is defined as "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."[154]

Canada edit

In Canada, modafinil is not listed in the Controlled Drugs and Substances Act, but it is a Schedule F prescription drug,[155] so it is subject to seizure by Canada Border Services Agency.[155]

China edit

In mainland China, modafinil is strictly controlled like other stimulants such as amphetamines and methylphenidate. It is classified as Class I psychotropic drug,[156] meaning that only doctors who have the right to prescribe narcotics and Class I psychotropic drugs (usually through special examination) can prescribe it, for no more than three-day use (or seven-day use for control/extend-release products).[157]

Moldova edit

In The Republic of Moldova, modafinil is considered a psychotropic drug[158] but can be purchased with prescription, however, importing modafinil may be considered illegal psychotropic drug (narcotics) trafficking and can be punished by up to 8 years in prison, as warned by the Customs service of Moldova.[159] In order to determine the punishment, the quantities of up to 0,002g of modafinil are considered "small quantities", while quantities in the range of 0,002g to 1,0g are considered "large quantities".[158] In Transnistria, modafinil is a prohibited substance (similar to narcotics) regardless of prescription and possession of even a few pills can lead to imprisonment.[160]

Japan edit

In Japan, modafinil is Schedule I psychotropic drug.[161][162] Cephalon licensed Alfresa Corporation to produce, and Mitsubishi Tanabe Pharma to sell modafinil products under the trade name Modiodal in Japan.[163] There have been arrests of people who imported modafinil for personal use.[164][165]

Romania edit

Modafinil is considered a stimulant doping agent and, as such, is prohibited in sports competitions. It is in the same category as steroids.[166] Due to laws passed in 2022, import into the country or selling is considered a felony and can be punished with jail time from three to seven years.[167] Simple possession for personal use is punished with a fine and confiscation.[167]

Russia edit

In Russia, modafinil is Schedule II controlled substance like cocaine and morphine. Possession of a few modafinil pills can lead to three to ten years imprisonment.[160]

Sweden edit

In Sweden, modafinil is classified as a schedule IV substance; possession is illegal without prescription.[168]

United States edit

Modafinil is classified as a Schedule IV controlled substance under United States federal law.[6] It is illegal to import by anyone other than a DEA-registered importer without a prescription.[169] The Clinton administration issued regulations in 64 FR 4050 effective January 27, 1999, based upon a recommendation of the administration's Assistant Secretary for Health.[170]

A person may legally bring modafinil into the United States in person from a foreign country, provided that the person has a prescription for it, and the drug is properly declared at the border crossing. US residents are limited to 50 dosage units (e.g., pills).[171] Under the US Pure Food and Drug Act, drug companies are not allowed to market their drugs for off-label uses (treatments of conditions other than those officially approved by the FDA);[172] Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading".[173] Cephalon pleaded guilty to a criminal violation and paid several fines, including $50 million and $425 million fines to the US government in 2008.[174][175]

Other countries edit

The following countries do not classify modafinil as a controlled substance:

  • In Finland, modafinil is a prescription drug but not listed as a controlled substance.[176]
  • In Denmark, modafinil is a prescription drug but not listed as a controlled substance.[177]
  • Mexico (Not listed as a controlled substance, in the National Health Law. Can be purchased in pharmacies without prescription.)[178]
  • South Africa Schedule V[179]
  • United Kingdom (not listed in Misuse of Drugs Act so possession is not illegal, but a prescription is required) [180]

Brand names edit

A generic formulation of modafinil marketed under the Aspendos brand name

Modafinil is sold under a variety of brand names worldwide, including Alertec, Alertex, Altasomil, Aspendos, Bravamax, Forcilin, Intensit, Mentix, Modafinil, Modafinilo, Modalert, Modanil, Modasomil, Modvigil, Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, Waklert, and Zalux.[181]

Economics edit

The global sales figures for modafinil are not known, still, Modafinil sold under the brand name Provigil accounted for over 40% of Cephalon's global turnover for several years, according to the information published in 2020.[182]

The price of modafinil in some English-speaking countries is the following:

  • USA: The cost for modafinil 200 mg tablets is around $217 for a supply of 20 tablets,[183] prices start at $28.61.[184]
  • UK: The cost of modafinil 100mg tablets is £18.05 for a supply of 20 tablets.[185]
  • Canada: Most pharmacies will charge an arm and a leg for brand name modafinil — which can be as high as $65 CAD for a supply of 20 tablets of 100 mg.[186]
  • Australia: The cost of modafinil 100mg is $110.99 for a supply of 60 tablets.[187]

Sports edit

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 tested positive for the substance. Some athletes who used modafinil protested that the drug was not on the prohibited list at the time of their offenses.[188] However, the World Anti-Doping Agency (WADA) maintains that modafinil 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.

Several athletes (such as sprinter Kelli White in 2003, cyclist David Clinger[189] and basketball player Diana Taurasi[190] in 2010, and rower Timothy Grant in 2015[191]) were accused of using modafinil as a performance-enhancing doping agent. Taurasi and another player—Monique Coker, tested at the same lab—were later cleared.[192] Kelli White, who tested positive after her 100m victory at the 2003 World Championships in Paris, was stripped of her gold medals.[193] She claimed that she used modafinil to treat narcolepsy, but the International Association of Athletics Federations (IAAF) ruled that modafinil was a performance-enhancing drug.[193]

The BALCO scandal brought to light an 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.[194]

In a study on 15 healthy male subjects, published in Medicine & Science in Sports & Exercise, an academic journal, acute ingestion of modafinil of 4 mg·kg−1 (at a dose of 4 mg per kilogram of body weight), prolonged exercise time to exhaustion while performing at 85% of VO2max threshold, and also reduced the perception of effort required to maintain this threshold, [195] i.e., the control subjects were able to perform at 85% of their maximum oxygen consumption without feeling as much effort as without modafinil (with placebo).[195]

Social views edit

The use of modafinil as a supposed cognitive enhancer is viewed differently among various groups.[196] Some groups consider such use as cheating, unnatural, or risky.[197] For instance, some academic institutions such as University of Sussex in the UK have explored this question raised by the students, although the university do not have a strong, official stance on its use, explaining that it is a prescription drug and the decision should be made by the doctor on whether to prescribe modafinil to a student.[198] In the realm of bioethics, the President's Council on Bioethics in the US, chaired by Leon Kass, argued that excellence achieved through the use of drugs like modafinil is "cheap" as it obviates the need for hard work and study, and is not fully authentic because the excellence is partly attributable to the drug, not the individual.[199] On the other hand, some people, particularly those in high-pressure environments like Wall Street traders, do not view the use of modafinil as cheating. They argue that if modafinil can give them an edge and they are aware of the risks involved, it should not be considered as cheating.[200] Due to such varying views, modafinil users for nacrolepsy may cope with stigma by hiding, denying, or justifying their use, or by seeking support from others who share their views or experiences.[201][202]

Music and entertainment edit

Peter Cullen, is an American-Canadian voice actor, wrote "Modafinil - Music to Mod to", an instrumental electronic composition influenced by modafinil.[203] Matthew Dear an American electronic music producer and DJ, wrote "Modafinil Blues", an indie rock song.[204] Joe Rogan, an American comedian, podcaster, and mixed martial arts commentator, has talked about modafinil on his show The Joe Rogan Experience.[205][206][207]

Research edit

Psychiatric conditions edit

Major depression edit

Modafinil has been studied in the treatment of major depressive disorder.[208][209][210] In a 2021 systematic review and meta-analysis of randomized controlled trials of psychostimulants for depression, modafinil and other stimulants such as methylphenidate and amphetamines improved depression in traditional meta-analysis.[210] However, when subjected to network meta-analysis, modafinil and most other stimulants did not significantly improve depression, with only methylphenidate remaining effective.[210] Modafinil and other stimulants likewise did not improve quality of life in the meta-analysis, although there was evidence for reduced fatigue and sleepiness with modafinil and other stimulants.[210] While significant effectiveness of modafinil for depression has been reported,[211][212][209] reviews and meta-analyses note that the effectiveness of modafinil for depression is limited, the quality of available evidence is low, and the results are inconclusive.[213][210]

Bipolar depression edit

Modafinil and armodafinil have been repurposed as adjunctive treatments for acute depression in people with bipolar disorder.[113] A 2021 meta-analysis concluded that add-on modafinil and armodafinil were more effective than placebo on response to treatment, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence is therefore low, limiting the clinical relevance of the evidence.[113] Very low rates of mood switch (a change in mood from one extreme to another)[214] have been observed with modafinil and armodafinil in bipolar disorder.[212]

Attention deficit hyperactivity disorder edit

Modafinil was seriously considered for the treatment of attention deficit hyperactivity disorder (ADHD) because of its lower abuse potential than conventional psychostimulants like methylphenidate and amphetamines.[215][216] In 2008, an application to market modafinil for pediatric ADHD was submitted to the Food and Drug Administration in the USA.[60]

However, evidence of modafinil for treatment of adult ADHD is mixed, and a 2016 systematic review of alternative drug therapies for adult ADHD did not recommend its use in this context.[217] In a later large phase 3 clinical trial of modafinil for adult ADHD, modafinil was not effective in improving symptoms, and there was a high rate of side effects (86%) and discontinuation (47%).[218] The poor tolerability of modafinil in this study was possibly due to the use of excessively high doses (210–510 mg/day).[218] Another reason for the denial of the approval was due to concerns about rare but serious dermatological toxicity (Stevens–Johnson syndrome).[60]

Nevertheless, because modafinil has an approved use in the US, medical doctors can legally prescribe it for off-label use, such as to treat ADHD in both children and adults.[219][215][220]

Substance dependence edit

Modafinil was studied for the treatment of stimulant dependence, but the results are mixed and inconclusive.[108][221]

Treatment of cocaine addiction edit

Modafinil has been studied for the treatment of cocaine addiction. Modafinil binds to the dopamine transporter (DAT) in an open-to-out conformation, differently than cocaine and methylphenidate.[222][223][224] Subjects pretreated with modafinil report experiencing less euphoria from cocaine administration.[223] Modafinil does not potentiate self-administration of cocaine in pretreated rats.[225]

The mechanism by which modafinil inhibits cocaine self-administration is likely more complex than the simple observation that modafinil occupies the DAT, as drugs like methylphenidate (another dopamine re-uptake inhibitor (DRI) fail to reduce cocaine self-administration.[222][226] Atypical DRIs like modafinil that bind to the DAT in an open-to-out conformation often lack abuse potential relative to cocaine-like DAT ligands.[227]

Schizophrenia edit

Modafinil and armodafinil were studied as a complement to antipsychotic medications in the treatment of schizophrenia. They showed no effect on positive symptoms or cognitive performance.[228][229] A 2015 meta-analysis found that modafinil and armodafinil may slightly reduce negative symptoms in people with acute schizophrenia, though they do not appear useful for people with the condition who are stable, with high negative symptom scores.[229] Among medications demonstrated to be effective for reducing negative symptoms in combination with antipsychotics, modafinil and armodafinil are among the smallest effect sizes.[230]

Cognitive enhancement edit

A 2015 review of clinical studies of possible nootropic effects in healthy people found: "...whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function, only half show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes."[13] A 2019 review of studies of a single-dose of modafinil on mental function in healthy, non-sleep-deprived people found a statistically significant but small effect and concluded that the drug has limited usefulness as a cognitive enhancer in non-sleep-deprived persons.[231] A 2020 review of the cognitive enhancing potential of methylphenidate, d-amphetamine, and modafinil in healthy individuals across various domains found that modafinil has a small, positive effect on memory updating.[232]

Modafinil has been used off-label in trials with people with post-chemotherapy cognitive impairment, also known as "chemobrain", but a 2011 review found that it was no better than a placebo.[233]

Post-anesthesia sedation edit

General anesthesia is required for many surgeries, but may cause lingering fatigue, sedation, and/or drowsiness after surgery that lasts for hours to days. In outpatient settings in which patients are discharged home after surgery, this sedation, fatigue, and occasional dizziness is problematic, but it was only tested in one small study, and the results are inconclusive.[219]

Multiple sclerosis-related fatigue (research) edit

Modafinil was studied for use in multiple sclerosis-associated fatigue, but the resulting evidence was weak and inconclusive.[234][235][236] There were two small controlled studies with conflicting results, and no large, long-term, randomized controlled studies.[25] Therefore, the benefit of using modafinil for the treatment of multiple sclerosis-related fatigue was not confirmed.[25]

Postural orthostatic tachycardia syndrome edit

Caution should be exercised in patients who have narcolepsy in comorbidity with postural orthostatic tachycardia syndrome (POTS). Modafinil, like other centrally acting stimulants prescribed for patients in narcolepsy, increases POTS-related autonomic dysfunction and results in tachycardia/arrhythmia side effects in patients with cardiovascular risk factors. Sodium oxybate, a metabolite of GABA, is an alternative drug for stimulant-intolerant patients with POTS.[237]

Inflammation edit

There is limited research on the potential use of modafinil as an anti-inflammatory agent,[238][239] even though some studies predict that modafinil may have anti-inflammatory effects.[240][241]

One probable explanation of the drug's supposed anti-inflammatory properties is that that modafinil may modulate the production of nitric oxide in various cells, potentially leading to anti-inflammatory effects.[241][242] Nitric oxide is a signaling molecule that plays a complex role in inflammation.[243][244] It is produced by a variety of cells in the body, including immune cells,[245] and can have both pro-inflammatory and anti-inflammatory effects depending on the context.[246][247] In a 2018 study, researchers noticed that modafinil reduced the production of pro-inflammatory cytokines in vitro in mouse brain cells.[248] In a 2020 study, scholars observed modafinil reduced inflammation and oxidative stress in the brains of rats with traumatic brain injury.[249] In a 2023 study, modafinil reduced neuroinflammation in rats induced by propionic acid.[250]

Another probable explanation is that modafinil may exert anti-inflammatory effects by upregulating adenosine A2A and A2B receptors. These receptors activate cyclic adenosine monophosphate signaling, which suppresses inflammation and fibrosis. This suggests that modafinil's ability to upregulate these receptors may serve as a potential therapy for fibrotic diseases.[251] In a 2020 in vitro study, using in nonalcoholic hepatitis human cell model, the authors predicted that modafinil may reduce inflammatory and fibrotic progression in the human liver.[239]

The results of studies on the potential anti-inflammatory properties of modafinil still need to be more conclusive.[239]

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