Modafinil: 5 Things You Should Know About

Modafinil, sold under the brand name Provigil among others, is a medication to treat sleepiness due to narcolepsy, shift work sleep disorder, or obstructive sleep apnea. While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive. It is taken by mouth.

Was approved for medical use in the United States in 1998.

Uses

In 2017, modafinil was the 328th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions. In the United Kingdom it costs the NHS about £105.21 a month as of 2018.

Medical

It is a eugeroic used for treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.

For obstructive sleep apnea, it is recommended that continuous positive airway pressure be appropriately used before considering starting modafinil to help with daytime sleepiness.

Modafinil

Occupational use

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 where troops face sleep deprivation. The French government indicated that the Foreign Legion used modafinil during certain covert operations. The United Kingdom’s Ministry of Defence commissioned research into modafinil from QinetiQ and spent £300,000 on one investigation. In 2011, the Indian Air Force announced that modafinil was included in contingency plans.

In the United States military, modafinil Buy It has been approved for use on certain Air Force missions, and it is being investigated for other uses. As of November 2012, It is the only drug approved by the Air Force as a “go pill” for fatigue management .

The Canadian Medical Association Journal also reports that modafinil is used by astronauts on long-term missions aboard the International Space Station. Modafinil is “available to crew to optimize performance while fatigued” and helps with the disruptions in circadian rhythms and with the reduced quality of sleep astronauts experience.

Adverse effects and contraindications

It is contraindicated in people with known hypersensitivity to modafinil or armodafinil. Modafinil 200mg is not approved for use in children for any medical conditions.

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% to 10% of users may be affected with anxiety, insomnia, dizziness, diarrhea, and rhinitis.

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, Stevens–Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome, involving adult and pediatric patients.

The FDA issued a relevant alert. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experiences. In 2007, the FDA ordered Cephalon to modify the Provigil leaflet in bold-face print of several serious and potentially fatal conditions attributed to modafinil use, including TEN, DRESS syndrome, and SJS.

The long term safety and effectiveness of modafinil have not been determined.

It may have an adverse effect on hormonal contraceptives for up to a month after discontinuation.

Addiction and dependence

The addiction and dependence liabilities of modafinil are relatively low. As such, It is classified by the United States FDA as a schedule IV controlled substance, a category for drugs with valid medical uses and low but significant addiction potential.

Tolerance

Large-scale clinical studies have found no evidence of tolerance with modafinil at therapeutic dosages even with prolonged use .

Psychiatric reactions

Modafinil-associated psychiatric reactions have occurred in those with and without a pre-existing psychiatric history.

Overdose

In mice and rats, the median lethal dose of Sun pharma modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values reported for rats range from 1000 to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. Clinical trials on humans involving taking up to 1200 mg/day for 7–21 days and known incidents of acute one-time overdoses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea.

Dopamine transporter blocker

Research found that It elevates dopamine levels in the hypothalamus in animals. The locus of the monoamine action of modafinil was also the target of studies, with effects identified on dopamine in the striatum and, in particular, nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex. It was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology.

Of the sites tested, it was found to significantly affect only the dopamine transporter, acting as a dopamine reuptake inhibitor with an IC50 value of 4 μM. In accordance, increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine and also inhibits methamphetamine-induced dopamine release.

As such, “modafinil is an exceptionally weak, but apparently very selective,  inhibitor”. In addition to animal research, a human positron emission tomography imaging study found that 200 mg and 300 mg doses of modafinil resulted in DAT occupancy of 51.4% and 56.9%, respectively, which was described as “close to that of methylphenidate”. Another human PET imaging study similarly found that it occupied the DAT and also determined that it significantly elevated extracellular levels of dopamine in the brain, including in the nucleus accumbens.

It has been described as an “atypical” DAT inhibitor, and shows a profile of effects that is very different from those of other dopaminergic stimulants. For instance, It produces wakefulness reportedly without the need for compensatory sleep, and shows a relatively low, if any, In addition, modafinil fails to reverse reserpine-induced akinesia, whereas dextroamphetamine, a dopamine releasing agent, is able to do so. Moreover, one of the first published structure-activity relationship studies of modafinil found in 2012 that DAT inhibition did not correlate with wakefulness-promoting effects in animals among modafinil analogues, and a variety of analogues without any significant inhibition of the DAT still produced wakefulness-promoting effects.

Furthermore, ” neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory”, and a study found that modafinil-induced increased locomotor activity in animals was dependent on histamine release and could be abolished by depletion of neuronal histamine, whereas those of methylphenidate were not and could not be. However, It sulfone lacks any wakefulness-promoting effects in animals, indicating that a distinct mechanism may be at play in the anticonvulsant effects of both compounds. The -enantiomer is inactive with respect to the D2 receptor.

Modafinil

Research

An in vitro study predicts that it may induce the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as may inhibit CYP2C9 and CYP2C19. The bioavailability of modafinil is greater than 80% of the administered dose. In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage actually changes very little when the concentration is varied.

None of these findings have been confirmed in vivo in clinical studies yet.

Pharmacokinetics

Cmax  occurs approximately 2–3 hours after administration. Food slows absorption, but does not affect the total AUC. Half-life is generally in the 10–12 hour range, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors.

Both of these metabolites have been described as inactive, and neither appear to contribute to the wakefulness-promoting effects of modafinil. However, modafinil sulfone does appear to possess anticonvulsant effects, and this is a property that it shares with modafinil. As of 2011, it is not specifically tested for by common drug screens and is unlikely to cause false positives for other chemically-unrelated drugs such as substituted amphetamines.

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