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= Modafinil =
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Introduction
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Modafinil, sold under the brand name Provigil among others, is a
central nervous system (CNS) stimulant and eugeroic (wakefulness
promoter) medication used primarily to treat narcolepsy, a sleep
disorder characterized by excessive daytime sleepiness and sudden
sleep attacks. Modafinil is also approved for stimulating wakefulness
in people with sleep apnea and shift work sleep disorder. It is taken
by mouth. Modafinil is not approved by the US Food and Drug
Administration (FDA) for use in people under 17 years old.
Common side effects of Modafinil include anxiety, insomnia, dizziness,
and headache. Modafinil has potential for causing severe allergic
reactions, psychiatric effects, hypersensitivity, adverse interactions
with prescription drugs, and misuse or abuse. Modafinil may harm the
fetus if taken during or two months prior to pregnancy.
While modafinil is used as a cognitive enhancer, or "smart drug,"
among healthy individuals seeking improved focus and productivity, its
use outside medical supervision raises concerns regarding potential
misuse or abuse. Research on the cognitive enhancement effects of
modafinil in non-sleep deprived individuals has yielded mixed results,
with some studies suggesting modest improvements in attention and
executive functions, while others show no significant benefits or even
a decline in cognitive functions at high doses.
Sleep disorders
=================
Modafinil, a eugeroic or wakefulness-promoting drug, is primarily used
for treating narcolepsy, a sleep disorder characterized by excessive
daytime sleepiness and sudden sleep attacks. Being a central nervous
system (CNS) stimulant itself, modafinil has lower addictive potential
than classical stimulants such as amphetamine, cocaine, or
methylphenidate, but still produces psychoactive, euphoric, and
subjective effects typical of classical stimulants.
Narcolepsy causes a strong urge to sleep during the day and can
include symptoms like cataplexy (sudden muscle weakness), sleep
paralysis (inability to move or speak while falling asleep or waking
up), and hallucinations. Narcolepsy is linked to a lack of the brain
chemical hypocretin (orexin), primarily produced in the hypothalamus.
Modafinil is not a cure for narcolepsy, but it can help manage the
symptoms. While modafinil is primarily used to treat excessive
sleepiness, it may also help reduce the frequency and severity of
cataplexy attacks in some people. Modafinil is approved for management
of narcolepsy with or without cataplexy. However, it is not
specifically approved for the treatment of cataplexy.
Modafinil is also prescribed for shift work sleep disorder.
Modafinil performs moderately (but better than armodafinil or
solriamfetol) as a drug to overcome excessive daytime sleepiness
caused by obstructive sleep apnea, though it is recommended that
people with apnea use continuous positive airway pressure (CPAP)
therapy, that is a sleep breathing apparatus to prevent apnea, before
starting modafinil. When obstructive sleep apnea is comorbid with
narcolepsy, modafinil is an effective drug to reduce the associated
excessive daytime sleepiness.
Modafinil's use varies by region. In the US, it is approved for adult
narcolepsy, shift work sleep disorder, and obstructive sleep apnea,
but not for children. In the UK and the EU, since 2014, it is approved
solely for narcolepsy, including in children (pediatric narcolepsy),
with its use for other conditions restricted by the European Medicines
Agency.
both the French and the American Academy of Sleep Medicine strongly
recommend modafinil as the first-choice treatment for narcolepsy. In
Europe, modafinil is considered one of the primary drugs recommended
for treating narcolepsy according to the guidelines.
Multiple sclerosis-related fatigue
====================================
The National Institute for Health and Care Excellence (NICE) in the
UK, along with various non-governmental organizations focused on
multiple sclerosis (MS), endorse the off-label use of modafinil to
alleviate fatigue associated with MS.
MS-related fatigue is a common and often debilitating symptom
experienced by people with multiple sclerosis. It can significantly
impact their daily functioning, quality of life, and ability to
perform everyday activities. When prescribed for MS-related fatigue
management, modafinil works by promoting wakefulness and increasing
alertness without causing drowsiness or disrupting nighttime sleep.
People with multiple sclerosis often report increased energy levels,
reduced feelings of tiredness, improved cognitive function, and an
overall improvement in their quality of life when taking modafinil.
While modafinil can provide relief from MS-related fatigue symptoms,
it does not treat the underlying cause or cure MS itself. The primary
goal of using modafinil in MS is symptom management and improving
daily functioning. The effects of modafinil on other aspects of
MS-related fatigue, such as severity and cognitive function, are less
clear.
While modafinil has been shown to be effective in managing fatigue in
people with MS, optimal dosing and treatment schedules are not well
established.
Attention deficit hyperactivity disorder
==========================================
Modafinil is occasionally prescribed off-label for individuals with
attention deficit hyperactivity disorder (ADHD). It has not
consistently shown efficacy in treating adult ADHD, especially when
compared to other treatments such as lisdexamfetamine. In children,
modafinil is efficient in treating ADHD symptoms.
Given its approved status in the US to treat narcolepsy, physicians
can also prescribe modafinil for off-label uses, such as treating ADHD
in both children and adults.
The Canadian Network for Mood and Anxiety Treatments (CANMAT) suggests
modafinil as a second-line choice for ADHD, after the first-line
choices such as bupropion are exhausted.
Bipolar disorder
==================
Modafinil is used off-label as an adjunctive treatment (i.e., in
combination therapy) for acute depressive phase in bipolar disorder.
The depressive phase of bipolar disorder may feature excessive
sleepiness and fatigue. Adjunctive treatment with modafinil can be
used as an augmentation for the main treatment to increase its effect
and is safe and effective, especially for people who do not respond
well to standard antidepressants. Modafinil does not significantly
increase the risk of mood switch to mania or suicide attempts in
people with bipolar disorder. Modafinil may also have cognitive
benefits in people with bipolar disorder who are in a remission state.
Whereas modafinil and armodafinil are approved for narcolepsy, they
have been repurposed as adjunctive treatments to alleviate symptoms of
acute depressive phase in people with bipolar disorder. Drug
repurposing in psychiatry is a strategy for discovering new uses for
drugs that have already been approved or tested in clinical trials for
other illnesses. As such, drug repurposing is a rapid, cost-effective,
and reduced-risk strategy for the development of new treatment options
for psychiatric disorders. 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. Very low rates of mood swing (a change in
mood from one extreme to another) have been observed with modafinil
and armodafinil in depressive phase of bipolar disorder.
Occupational
==============
Modafinil was used by the French Foreign Legion, US Air Force, and US
Marine infantry during the Gulf War to enhance "operational tempo" (a
term that denotes the speed and intensity at which military operations
or activities are executed), aiming to optimize the overall
performance and efficiency of the unit.
Armed forces in various countries, including the United States, the
United Kingdom, India, and France, have considered modafinil as an
alternative to traditional amphetamines for managing sleep deprivation
in combat or extended missions. The US military approved modafinil for
specific Air Force missions, replacing amphetamines for fatigue
management. The use of modafinil in military contexts without sleep
deprivation is not recommended due to inconclusive evidence on its
cognitive enhancement benefits and potential risks of adverse effects.
Modafinil is also available to astronauts aboard the International
Space Station for the management of fatigue caused by circadian
dyssynchrony in orbit.
Non-medical
=============
Modafinil has been used non-medically as a "smart drug" by various
groups, including students, office workers, transhumanists, and
professionals in various sectors. Its use is attributed by these
individuals to its potential for enhancing attention, cognitive
capabilities, and alertness.
The effectiveness of modafinil as cognitive enhancer is still debated.
Some studies suggest significant increases in cognitive abilities,
while others indicate mild to non existent cognitive improvements. In
some cases, it has even been associated with impairments in certain
cognitive functions. It has been shown that modafinil's positive
impact on cognitive abilities is more noticeable on sleep deprived
individuals. Therefore, in people who are not sleep-deprived, the
potential of modafinil as a cognitive enhancer may be limited.
Adverse effects
======================================================================
Modafinil is generally well-tolerated but can have potential risks and
side effects. Common adverse effects of modafinil, experienced by less
than 10% of users, include headaches, nausea, and reduced appetite.
Anxiety, insomnia, dizziness, diarrhea, and rhinitis are also reported
in 5% to 10% of users. Psychiatric reactions have occurred in
individuals with and without a preexisting psychiatric history.
No significant changes in body weight have been observed in clinical
trials, although decreased appetite and weight loss have been noted in
children and adolescents. Modafinil can cause a slight increase in
aminotransferase enzymes, indicative of liver function, but there is
no evidence of serious liver damage when levels are within reference
ranges.
Rare but serious adverse effects include severe skin rashes and
allergy-related symptoms. Between December 1998 and January 2007, the
FDA received reports of six cases of severe cutaneous adverse
reactions, including erythema multiforme, Stevens-Johnson syndrome,
toxic epidermal necrolysis, and DRESS syndrome. The FDA has issued
alerts regarding these risks and also noted reports of angioedema and
multi-organ hypersensitivity reactions in postmarketing surveillance.
In 2007, the FDA required Cephalon to modify the Provigil leaflet to
include warnings about these serious conditions. The long-term safety
and effectiveness of modafinil have not been conclusively established.
The FDA does not endorse modafinil for children's medical conditions
due to an increased risk of rare but serious dermatological toxicity,
manifested as Stevens-Johnson syndrome which is a type of severe skin
reaction. However, in Europe, modafinil may be prescribed for treating
narcolepsy in children.
Available forms
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Modafinil is commercially available in and oral tablet forms.
Additionally, it is offered as the ('R')-enantiomer, known as
armodafinil, and as a prodrug named adrafinil.
Contraindications
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Modafinil is contraindicated during pregnancy and 2 months before
getting pregnant. Women who take modafinil should not become pregnant,
and, additionally, should be aware that modafinil reduces
effectiveness of hormonal contraceptives, increasing chances of
getting pregnant. Modafinil therapy during pregnancy increases the
risk of birth defects, such as with congenital torticollis,
hypospadias, and congenital heart defects.
Modafinil is contraindicated for individuals with known
hypersensitivity to either modafinil or armodafinil.
Modafinil is also contraindicated in certain cardiac conditions,
including uncontrolled moderate to severe hypertension, arrhythmia,
cor pulmonale, and in cases with signs of CNS stimulant-induced mitral
valve prolapse or left ventricular hypertrophy. The package insert in
the United States cautions about using modafinil in people with a
documented medical history of left ventricular hypertrophy or those
diagnosed with mitral valve prolapse who have previously exhibited
symptoms associated with the mitral valve prolapse syndrome while
undergoing treatment involving central nervous system stimulants. The
reasons why modafinil is contraindicated in certain cardiac conditions
are because modafinil affects the autonomic nervous system and, in
particular, exerts significant effects on autonomic cardiovascular
regulation, leading in some people to notable increases in heart rate
and blood pressure. These substantial changes in the autonomic system
warrant careful consideration when prescribing modafinil to people
with pre-existing cardiovascular conditions. The increase in heart
rate and blood pressure can worsen the symptoms of such pre-existing
conditions as hypertension, arrhythmia, and cor pulmonale. These
changes in the autonomic system induced by modafinil can increase the
risk of heart attack, stroke, and heart failure. Modafinil can
stimulate the release of norepinephrine and epinephrine, hormones that
activate the sympathetic nervous system. This can cause
vasoconstriction, which is the narrowing of blood vessels, and
increase the heart's workload, which is not desired in people with
pre-existing heart conditions. In particular, modafinil can worsen the
consequences of mitral valve prolapse or left ventricular hypertrophy,
which are structural abnormalities of the heart. These can affect the
blood flow and oxygen delivery to the heart and other organs.
Modafinil is also contraindicated in people with congenital problems
like galactose intolerance, lactase deficiency, or glucose-galactose
malabsorption.
Drug tolerance
======================================================================
Extensive clinical research has not demonstrated drug tolerance as a
common adverse effect, even with therapeutic use extending up to 40
weeks. Drug tolerance in this context is defined as a reduction in
response, to wakefulness-promoting and anti-fatigue properties of
modafinil.
While modafinil is generally found to be safe and significant adverse
effects are rare, including in pediatric narcolepsy cases (sleep
disorders in children), there is evidence that long-term usage can
lead to tolerance in some individuals. This necessitates higher doses
to maintain the same level of cognitive enhancement or relief from
sleepiness.
People with current or past substance addictions and those with a
family history of addiction are particularly at risk for developing
tolerance.
The mechanisms driving tolerance to modafinil, which may involve its
impact on dopamine and norepinephrine levels in the brain, are not
fully understood.
Repeated administration of modafinil for off-label use, such as
increased alertness and cognitive-enhancing effects in sleep
deprivation, can lead to drug tolerance, which means that the
effectiveness of the drug may decrease over time. Still, modafinil
therapy as a eugeroic agent to treat narcolepsy does not typically
lead to drug tolerance, i.e., the effectiveness does not usually
decrease on prolonged use, although individual responses may vary.
Addiction and dependence
======================================================================
Despite being a CNS stimulant, the addiction and dependence
liabilities of modafinil are considered low. The exact mechanisms of
action of modafinil are not known, and it is believed that
pharmacological profile of modafinil is different from that of the
classical stimulants such as cocaine or amphetamine. Although
modafinil shares biochemical mechanisms with stimulant drugs, it is
less likely to have mood-elevating properties. The similarities in
effects with caffeine are not clearly established. Unlike other
stimulants, modafinil does not induce a strong subjective feeling of
pleasure or reward, which is commonly associated with euphoria, an
intense feeling of well-being. Euphoria may be an indicator of a
drug's potential to be abused, which is the compulsive and excessive
use of a substance despite adverse consequences. In comparison to
classical stimulants, modafinil exhibits a low propensity for abuse,
as it lacks significantly expressed pleasurable or euphoric effects.
Albeit to a lower degree than classical stimulants, modafinil still
can produce psychoactive, euphoric, and subjective effects typical for
abused stimulants.
Modafinil was not observed to promote overuse or misuse, even in
people who have a history of cocaine addiction. Despite the initial
belief that modafinil carried no abuse potential, emerging evidence
suggests that it works at the same neurobiological mechanisms as other
addictive stimulants. Consequently, there exists a potential risk of
modafinil abuse, necessitating prudent consideration and caution when
prescribing or using this medication. Modafinil exhibits a lower
response on the amphetamine scale of the addiction research center
inventory, suggesting reduced propensity for abuse compared to
amphetamine.
The US Drug Enforcement Administration has classified modafinil as a
Schedule IV controlled substance; the medicine is recognized for
having valid medical uses with low addiction potential. The
International Narcotics Control Board does not classify it as a
narcotic or a psychotropic substance.
Overdose
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An overdose of modafinil can lead to a range of symptoms and
complications. Psychiatric symptoms may include psychosis, mania,
hallucinations, and suicidal ideation, which can occur even in
individuals without a history of mental illness and may persist after
discontinuation of the drug. Neurological complications, such as
seizures, tremors, dystonia, and dyskinesia, may arise from
modafinil's interaction with various neurotransmitter systems.
Allergic reactions such as rash, angioedema, anaphylaxis, and
Stevens-Johnson syndrome may rarely be triggered by an immunological
response to modafinil or its metabolites. Cardiovascular complications
like hypertension, tachycardia, chest pain, and arrhythmias may also
be observed due to modafinil's sympathomimetic action.
In animal studies, the median lethal dose (LD50) of modafinil varies
among species and depends on the route of administration. In mice and
rats, the LD50 is approximately if administered via an injection, but
the oral LD50 for rats is . The LD50 value for humans have not been
established. Human clinical trials have involved total daily doses up
to for 7-21 days. Acute one-time total overdoses up to have not been
life-threatening but resulted in symptoms like agitation, insomnia,
tremor, palpitations, and gastrointestinal disturbances.
The management of modafinil overdose involves supportive care,
monitoring of vital signs, and treatment of specific complications. In
cases of recent consumption, activated charcoal, gastric lavage, or
hemodialysis may be used. There is no specific antidote for modafinil
overdose. The main way to deal with modafinil overdose is supportive
care, which includes sedating the patient and stabilizing their blood
pressure, and muscle activity in case of manifestations such as
agitation or tremor.
Interactions
======================================================================
Some of the drugs that frequently interact with modafinil include
aripiprazole (an antipsychotic), amphetamine (including its
enantiomers and salts; stimulants), aspirin, diphenhydramine (an
antihistamine), and others.
Modafinil is a weak to moderate inducer of CYP3A4 and a weak inhibitor
of CYP2C19, enzymes of the cytochrome P450 group of enzymes. 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.
However, other in-vitro studies find no significant inhibition of
CYP2C9. Modafinil may induce P-glycoprotein, which may affect drugs
transported by P-glycoprotein, such as digoxin.
It was clinically found that modafinil affects pharmacodynamics of
drugs which are metabolized by CYP3A4 and other enzymes of the
cytochrome P450 family, so that interactions of modafinil with these
drugs were observed in real people, rather than being predicted in a
lab setting. For instance, it was observed that induction of CYP3A4 by
modafinil affects metabolism of the following medications and
endogenous substances:
* opioids, such as methadone, hydrocodone, oxycodone, or fentanyl -
modafinil may result in a drop in opioid plasma concentrations because
of faster clearance of opioids by CYP3A4. If the patient is not
monitored closely, reduced efficacy or withdrawal symptoms can occur.
* steroid hormones, such as estradiol, progesterone or cortisol.
Modafinil may have an adverse effect on hormonal contraceptives (such
as birth control pills, patches, etc.) for up to a month after
discontinuation. Both modafinil and armodafinil in the United States
and the United Kingdom come with package inserts that highlight the
interaction between these medications and hormonal birth control.
Modafinil may induce cytochrome P450 enzymes that are involved in the
clearance of steroid hormones taken as hormonal contraceptives,
reducing their effectiveness, which may lead to pregnancy despite
taking the birth control medication. Besides steroid hormones,
modafinil may affect pituitary gland hormones. In a 2006 study, a
single dose of modafinil caused a decrease in blood prolactin levels,
although it did not affect human growth hormone or thyroid-stimulating
hormone. Since modafinil induces the activity of the CYP3A4 enzyme
involved in cortisol clearance, modafinil may reduce the
bioavailability of hydrocortisone. Therefore, it may be necessary to
adjust the steroid substitution dose in people receiving modafinil,
which is a CYP3A4-metabolism-inducing drug.
Hypertensive crises have been reported when armodafinil (one of
modafinil's enantiomers) has been taken with monoamine oxidase
inhibitors (MAOIs) like tranylcypromine.
Pharmacodynamics
==================
Modafinil activity profile
Site !! Potency !! Type !! Species !! Refs
Ki Ki IC50a IC50a Human Rat Human Rat
> > Ki Ki IC50a IC50a Human Rat Human Rat
> > > Ki Ki IC50a IC50a Human Rat Human Rat
| **Footnotes:** a = Functional activity, not binding inhibition. b =
Armodafinil at D2High. **Notes:** No activity at a variety of other
assessed targets.
D2 > b b Ki Ki EC50a Human Rat Rat
The precise mechanism of action of modafinil for narcolepsy and other
sleep disorders remains unclear. Although modafinil may have
interactions with neurotransmitter systems, its exact mode of action
is not fully understood.
From laboratory research, modafinil has little to no affinity for
serotonin or norepinephrine transporters and does not directly
interact with these systems. However, studies have shown that elevated
concentrations of norepinephrine and serotonin can occur as an
indirect effect following modafinil administration due to increased
extracellular dopamine activity. Unlike traditional psychostimulant
drugs, such as cocaine or amphetamine, modafinil shows low potential
for causing euphoria due to differences in how it interacts with
dopamine transporters at a cellular level.
In addition to its influence on dopaminergic pathways, modafinil may
impact other neurotransmitter systems, such as orexin (hypocretin).
Orexin neurons play a crucial role in promoting wakefulness and
regulating arousal states. Modafinil may increase signaling within
hypothalamic orexin pathways, potentially contributing to its
wake-promoting effects.
Pharmacokinetics
==================
Cmax (peak levels) occurs approximately 2 to 3 hours after modafinil
administration. Food slows absorption of modafanil, but does not
affect the total area under the curve (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.
Renal excretion of unchanged modafinil usually accounts for less than
10% of an oral dose. This means that when modafinil is taken by mouth,
that is the only approved route of administration, less than 10% of
the drug is eliminated from the body through the urine without being
metabolized by the liver or other organs. The rest of the drug is
either metabolized or excreted through other routes, such as feces or
bile.
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 appears to
contribute to the wakefulness-promoting effects of modafinil. However,
modafinil sulfone does appear to possess anticonvulsant effects, a
property that it shares with modafinil.
Elimination half-life is in the range of 10 to 12 hours, subject to
differences in sex, in cytochrome P450 genotypes, liver function and
renal function. Modafinil is metabolized mainly in the liver, and its
inactive metabolites are 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.
Modafinil exhibits sex-specific pharmacokinetic differences. It
demonstrates higher bioavailability in women compared to men. The mean
Cmax is higher in women than in men, vs. (p < 0.05), following a
single oral dose of modafinil. This difference persists even after
adjusting for body weight ( vs. ). The clearance of modafinil is 30%
higher in men than in women, and plasma concentrations after a single
dose are significantly higher in women than in men. These sex-specific
pharmacokinetic differences may have implications for the efficacy and
safety of modafinil.
Enantiomers
=============
Modafinil is a racemic mixture of two enantiomers, armodafinil
(('R')-modafinil) and esmodafinil (('S')-modafinil).
Detection in body fluids
==========================
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. 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.
Reagent testing can screen for the presence of modafinil in samples.
Colors produced by modafinil with various reagents
!RC !Marquis Reagent !Liebermann !Froehde
|Modafinil Yellow/Orange > Brown Darkening Orange Deep
orange/red
Structural analogs
====================
Many derivatives and structural analogs of modafinil have been
synthesized. Examples include adrafinil, CE-123, fladrafinil
(CRL-40941; fluorafinil), flmodafinil (CRL-40940; bisfluoromodafinil,
lauflumide), RDS03-94, JJC8-088, modafiendz and modafinil sulfone
(CRL-41056).
History
======================================================================
Modafinil was developed in France by neurophysiology professor Michel
Jouvet and Lafon Laboratories. It is part of a series of benzhydryl
sulfinyl compounds, including adrafinil, initially used as a treatment
for narcolepsy in France in 1986. Modafinil, the primary metabolite of
adrafinil, has been prescribed in France since 1994 under the name
Modiodal, and in the United States since 1998 as Provigil. Unlike
modafinil, adrafinil does not have FDA approval and was withdrawn from
the French market in 2011.
The FDA approved modafinil in 1998 for narcolepsy treatment, and later
for shift work sleep disorder and obstructive sleep apnea in 2003. It
was approved in the UK in December 2002. In the United States,
modafinil is marketed by Cephalon, who acquired the rights from Lafon
and purchased the company in 2001.
Cephalon introduced armodafinil, the ('R')-enantiomer of modafinil, in
the United States in 2007. Generic versions of modafinil became
available in the US in 2012 after extensive patent litigation.
Society and culture
======================================================================
Modafinil is not approved for use by children in multiple
jurisdictions.
Australia
===========
In Australia, modafinil is considered to be a Schedule 4
prescription-only medicine. This means that it is a drug with a
perceived low potential for abuse and low risk of dependence; still,
the use of Schedule 4 drugs in Australia is restricted to those who
have a valid prescription from a medical practitioner; import from
abroad is illegal.
Canada
========
In Canada, modafinil is not specifically included in the lists of
controlled drugs and substances specified within the Controlled Drugs
and Substances Act. However, it is classified as a Schedule F
prescription drug. This means that modafinil can only be obtained
legally with a valid prescription from a licensed health care
practitioner in Canada, and the import of modafinil to Canada from
other countries is subject to restrictions: importing prescription
drugs without an import permit may result in the seizure of the drugs
at the border, the refusal of entry of the drugs into Canada, or
prosecution.
China
=======
In mainland China, modafinil is strictly controlled like other
stimulants such as amphetamines and methylphenidate. It is classified
as Class I psychotropic drug. This classification means that modafinil
is considered to have a high potential for abuse and dependence, and
is therefore subject to strict regulation and control. As a result,
modafinil is only available by prescription and cannot be purchased
over the counter. In order to obtain a prescription for modafinil, a
patient must have a valid medical reason for using the drug, such as
narcolepsy or obstructive sleep apnea. Additionally, the prescription
must be written by a licensed physician and filled at a licensed
pharmacy. The use of modafinil for non-medical purposes, such as with
the aim to improve cognitive performance or to stay awake for long
periods of time, is strictly prohibited and can result in legal
consequences.
Europe
========
In Denmark, modafinil is a prescription drug but not listed as a
controlled substance. According to the Danish Medicines Agency,
modafinil is approved for use in the treatment of narcolepsy, still,
importing modafinil to Denmark is considered illegal without a valid
prescription.
In Finland, modafinil is a prescription drug but not listed as a
controlled substance. Finland is a member of the European Union, and
it is illegal to import prescription medicine from outside the
European Union unless the person has a valid prescription.
In the Republic of Moldova, modafinil is classified as a psychotropic
drug (included in table III list 3 which is the list of psychotropic
substances as defined by the Government of Moldova) and is available
by prescription. Importation of modafinil may be considered illegal
and subject to severe penalties, even if you have a prescription. For
example, on June 29, 2017, Moldovan postal officers discovered 60
tablets of Modalert (200 mg modafinil tablets) in a parcel sent from
India to a resident in Chișinău, Moldova. The prohibited substance was
detected during a routine scan and was seized as illegal. The
authorities were notified of the incident and the recipient was
charged with criminal penalties. In the Transnistria region of
Moldova, modafinil is completely prohibited, due to application of the
legislation similar to that of Russia where modafinil is completely
prohibited and is in the same list as narcotics. Possession or an
attempt to bring modafinil to Transnistria potentially leads to
imprisonment.
In Romania, modafinil is classified as a stimulant doping agent and is
prohibited in sports competitions. In 2022, laws were passed making
its importation or sale a felony, punishable by three to seven years
in jail. Simple possession for personal use may result in a fine and
confiscation.
In Sweden, modafinil is classified as a schedule IV substance, which
means that it is considered to have low potential for abuse and low
risk of dependence. Still, possession is illegal without prescription.
In the United Kingdom, it is not listed in Misuse of Drugs Act, so
possession is not illegal, but a prescription is required.
Mexico
========
In Mexico, modafinil is not listed as a controlled substance, in the
National Health Law, and can be purchased in pharmacies without
prescription.
Japan
=======
In Japan, modafinil is Schedule I psychotropic drug. This means that
it is considered to have a high potential for abuse and dependence,
and is therefore subject to strict regulations. The use of Schedule I
drugs in Japan is generally prohibited, except under certain
circumstances, such as for medical purposes. It can only be prescribed
by a doctor. It cannot be imported or exported without a permit. It
cannot be used while driving or operating machinery. Cephalon licensed
Alfresa Corporation to produce, and Mitsubishi Tanabe Pharma to sell
modafinil products under the trade name Modiodal in Japan. There have
been arrests of people who imported modafinil for personal use.
Russia
========
In Russia, starting from May 18, 2012, modafinil is Schedule II
controlled substance. Being classified as a schedule II controlled
substance in Russia means that it is seen as a drug with a high
potential for abuse and dependence. This classification imposes strict
regulations on the production, distribution, and use of modafinil.
Possession of a few modafinil pills can lead to three to ten years
imprisonment. Modafinil is not approved for medical use in Russia and
cannot be bought even in pharmacies. It also cannot be imported from
abroad, even if you have a prescription issued outside Russia. There
are multiple cases of criminal proceedings initiated against Russian
residents who tried to import modafinil by mail from abroad.
South Africa
==============
In South Africa, modafinil is Schedule V substance, which means that
it is legal to use modafinil in South Africa, but only with a valid
prescription from a licensed medical practitioner.
United States
===============
In the United States, modafinil is classified as a schedule IV
controlled substance under US federal law. This means that the drug
has a low potential for abuse and dependence compared to other
controlled substances. However, it still requires a prescription from
a licensed healthcare provider to obtain.
It is illegal to import modafinil to the United States without a Drug
Enforcement Administration (DEA)-registered importer and a
prescription. Individuals may legally bring modafinil into the US from
a foreign country for personal use, limited to 50 dosage units, with a
prescription and proper declaration at the border. Under the Pure Food
and Drug Act, marketing drugs for off-label uses is prohibited.
Cephalon, the manufacturer of Provigil, faced legal issues for
promoting off-label uses and paid significant fines in 2008.
Brand names
=============
Modafinil is sold under a variety of brand names worldwide, including
Alertec, Alertex, Altasomil, Aspendos, Bravamax, Forcilin, Intensit,
Karim, Mentix, Modafinilo, Modalert, Modanil, Modasomil, Modvigil,
Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia,
Vigicer, Vigil, Vigimax, Waklert, and Zalux.
Economics
===========
Originally developed in the 1970s by French neuroscientist Michel
Jouvet and Lafon Laboratories, modafinil has been prescribed in France
since 1994, and was approved for medical use in the United States in
1998.
Concerns have been raised about the growing use of modafinil as a
"smart drug" or cognitive enhancer among healthy individuals who use
it with the aim to improve concentration and memory. In 2003,
modafinil sales were skyrocketing, with some experts concerned that it
had become a tempting pick-me-up for people looking for an extra edge
in a productivity-obsessed society. The cost of modafinil varied
depending on factors such as location and insurance coverage, still,
in 2004, the price of modafinil in the US was around $120 or more per
monthly supply. However, the availability of generic versions has
increased since then and may have driven down prices.
In 2020, modafinil was the 302nd most commonly prescribed medication
in the United States, with just over prescriptions.
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.
Patent protection and litigation
==================================
Modafinil's patent history involves several key developments. The
original patent, , was granted to Laboratoire L. Lafon in 1990,
covering the chemical compound of modafinil. This patent expired in
2010. In 1994, Cephalon filed a patent for modafinil in the form of
particles of a defined size, represented by , which expired in 2015.
Following the nearing expiration of marketing rights in 2002, generic
manufacturers, including Mylan and Teva, applied for FDA approval to
market a generic form of modafinil, leading to legal challenges by
Cephalon regarding the particle size patent. The patent RE 37,516 was
declared invalid and unenforceable in 2011.
In addition, Cephalon entered agreements with several generic drug
manufacturers to delay the sale of generic modafinil in the US. These
agreements were subject to legal scrutiny and antitrust
investigations, culminating in a ruling by the Court of Appeals in
2016, which found that the settlements did not violate antitrust laws.
Sports
========
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.
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 and basketball player Diana Taurasi in 2010, and rower Timothy
Grant in 2015, 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. Kelli White, who
tested positive after her 100m victory at the 2003 World Championships
in Paris, was stripped of her gold medals. 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.
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.
Social views
==============
The use of modafinil as a supposed cognitive enhancer may be
considered as cheating, unnatural, or risky. The University of Sussex
explained that it is a prescription drug and the decision should be
made by the doctor on whether to prescribe modafinil to a student. As
a matter of bioethics, the US President's Council on Bioethics 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. Alternately, people in environments like
Wall Street trading may not view the use of modafinil as cheating,
believing that if modafinil can give them an edge and they are aware
of the risks involved, it should not be considered as cheating. Due to
such varying views, modafinil users for narcolepsy may cope with
stigma by hiding, denying, or justifying their use, or by seeking
support from others who share their views or experiences.
Major depressive disorder
===========================
Modafinil has been studied in the treatment of major depressive
disorder. 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. However, when subjected to
network meta-analysis, modafinil and most other stimulants did not
significantly improve depression, with only methylphenidate remaining
effective. 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.
While significant effectiveness of modafinil for depression has been
reported by particular trials, 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.
Attention deficit hyperactivity disorder (research)
=====================================================
Modafinil was considered for the treatment of ADHD because of its
lower abuse potential than conventional psychostimulants like
methylphenidate and amphetamines. In 2008, an application to market
modafinil for pediatric ADHD was submitted to the Food and Drug
Administration in the US.
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. In a later large phase
3 clinical trial of modafinil for adult ADHD, modafinil was not
effective in improving symptoms, there was also a high rate of side
effects (86%) and discontinuation (47%). The poor tolerability of
modafinil in this study was possibly due to the use of high doses ().
Another reason for the denial of the approval was due to concerns
about rare but serious dermatological toxicity in Stevens-Johnson
syndrome.
The research on the use of modafinil for treating individuals with
Autism Spectrum Disorder (ASD) who also exhibit ADHD symptoms is
currently in its early stages with no results delivered.
Substance dependence
======================
Modafinil was studied for the treatment of stimulant dependence, but
the results are mixed and inconclusive. Modafinil is not a controlled
substance in some countries, unlike other medications, such as
bupropion, which is also used to treat depression and nicotine
dependence. The clinical trials that have tested modafinil as a
treatment for stimulant abuse have failed to demonstrate its efficacy
and the optimal dose and duration of modafinil treatment remain
unclear, and modafinil is not a recommended treatment for stimulant
abuse. 2024 reviews found that modafinil was ineffective for treating
individuals with amphetamine-type stimulant use disorder or
methamphetamine use disorder from these dependencies.
Schizophrenia
===============
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. 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. Among medications demonstrated to be
effective for reducing negative symptoms in combination with
antipsychotics, modafinil and armodafinil are among the smallest
effect sizes.
Abstinence in cocaine addiction
=================================
Modafinil is researched to determine whether it might improve
abstinence in people with cocaine addiction.
Motivational disorders
========================
Modafinil has been found to reverse tetrabenazine-induced motivational
deficits in animals and hence can produce pro-motivational effects.
Novel modafinil analogs with greater potency, including CE-123,
CE-158, JJC8-088, MK-26, and RDS03-94, have also been developed and
have shown pro-motivational effects in animals. These agents are of
potential interest in the treatment of motivational disorders in
humans.
Cognitive enhancement
=======================
A 2019 review conducted on the potential nootropic effects of
modafinil in healthy, non-sleep-deprived individuals revealed the
following: a) while studies using basic testing paradigms demonstrated
that modafinil enhances executive function, only half of these studies
showed improvements in attention, learning, and memory, with a few
studies even reporting impairments in divergent creative thinking; b)
modafinil displayed small levels of enhancement in attention,
executive functions, and learning abilities; c) no substantial side
effects or mood changes were observed; d) the available evidence
showed limited evidence for modafinil as a cognitive enhancer outside
of its use for sleep-deprived populations.
A 2020 review reported that modafinil has a modest effect on memory
updating, but the effect is small and may not accurately reflect the
perception that it is useful as a cognitive enhancer, as there is
insufficient evidence to support such a claim.
Post-anesthesia sedation
==========================
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 surgery the sedation, fatigue,
and occasional dizziness is problematic. Modafinil was tested as a
potential remedy to alleviate these symptoms. For example, it was
expected that modafinil would help people recover quicker from general
anesthesia after a short surgery, but the results were uncertain and
the inconclusive studies could not reliably verify the expectation.
The use of modafinil to relieve post-anesthesia sedation is
investigational.
Postural orthostatic tachycardia syndrome
===========================================
Caution should be exercised in people who have narcolepsy in
comorbidity with postural orthostatic tachycardia syndrome (POTS).
Myotonic dystrophy
====================
Modafinil is being researched as a potential remedy for excessive
daytime sleepiness in myotonic dystrophy (DM), an inherited condition
characterized by progressive muscle loss, weakness, and myotonia.
Myotonia is a condition where muscles cannot relax after they
contract. Myotonic dystrophy has two main types: DM1 (Steinert
disease) and DM2 (proximal myotonic myopathy). Both types can cause
excessive daytime sleepiness. Studies suggest that modafinil may be a
promising drug that can reduce both daytime sleepiness and myotonia
itself, without significant cardiac conduction effects, which is
crucial for patients with myotonic dystrophy who often have underlying
cardiac issues. Still, modafinil is not approved by FDA for use in
myotonic dystrophy, and the value and role of modafinil in DM remain
the subject of debate.
Disorders of consciousness
============================
Modafinil has been studied for its potential therapeutic effects in
patients with disorders of consciousness. Researchers are
investigating whether modafinil can stimulate neurotransmitters such
as histamine, norepinephrine, serotonin, dopamine, and orexin, and
whether modafinil has potential anti-oxidative effects.
Disorders of consciousness are states characterized by impaired
arousal and awareness. These states include coma, vegetative
state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious
state (MCS), cognitive motor dissociation, and covert cortical
processing. Brain injuries can impair consciousness through
neuroanatomic lesions involving the bilateral cerebral hemispheres,
rostral brainstem, diencephalon, or basal forebrain.
Neuroimaging studies have shown that modafinil increases cerebral
blood flow in several brain regions, such as the thalamus, locus
coeruleus, limbic system, and insular cortex; still, observational
reports on the use of modafinil in patients with disorders of
consciousness have produced mixed results, indicating that its
effectiveness may vary among individuals.
Inflammation
==============
A possible link between inflammatory processes and depressive
disorders has stimulated preliminary research on modafinil for its
potential anti-inflammatory effects.
License
=========
All content on Gopherpedia comes from Wikipedia, and is licensed under CC-BY-SA
License URL: http://creativecommons.org/licenses/by-sa/3.0/
Original Article: http://en.wikipedia.org/wiki/Modafinil