Modafinil and armodafinil are both classified as eugeroics (or wakefulness-promoting agents), and are used for the treatment of narcolepsy, shift work sleep disorder, and other sleep disorders. The most significant difference between them is that armodafinil has a longer half-life than modafinil.
This means it can be taken once per day instead of twice a day, as in the case of modafinil. In addition, armodafinil is not highly addictive. Modafinil, on the other hand, has a moderate risk for drug abuse or addiction.
Armodafinil was approved for medical use in 2007, and is marketed in the United States as Nuvigil, manufactured by Cephalon Inc. Modafinil was first introduced into the market in 1998.
Modafinil vs. Armodafinil - Half-life & Mechanism of Action
The structure of armodafinil is similar to that of modafinil, with a few differences. For instance, armodafinil is not a racemate (it contains only a single enantiomer) and is pure R-modafinil. Armodafinil has fewer side effects than modafinil, hence its use by patients has been more common than that of modafinil.
Modafinil has an elimination half-life of 13 to 15 hours, while armodafinil's elimination half-life is 15 to 20 hours. Both compounds have short onset periods between 15 to 45 minutes after ingestion. The longer half-life in armodifanfil makes it easier to manage on a daily basis.
Modafinil directly acts as a stimulant and increases extracellular concentrations of dopamine, serotonin, and norepinephrine in the brain.
Armodafinil blocks monoamine reuptake transporters, which results in increased levels of dopamine, norepinephrine, and serotonin.
This increases wakefulness and reduces sleep onset latency: it is, therefore, effective in treating shift workers, those with impaired sleep-wake cycles due to jet lag or other disturbances, or those suffering from clinical disorders.
Modafinil has a high affinity for the dopamine (DAT) transporter in the human brain. Dopamine is released by nerve cells after stimulation.
However, it is also taken up by nerve cells by means of sodium-dependent dopamine (NaDAT) transporters inside the cells. NaDAT is specific for DAT rather than other transporter proteins that also act on dopamine (e.g., vesicular monoamine transporter).
Pharmacological blockade of DAT by drugs like cocaine causes a sudden rise in extracellular dopamine levels, causing severe psychomotor activation and hyperthermia leading to physical collapse.
In contrast, agents like modafinil exert their effects slowly through a long-term block of NaDAT leading to significant side effects such as drowsiness and loss of motor coordination, which are not usually caused by an increase in the dopaminergic activity itself.
Modafinil has been demonstrated to be effective against major depression when used at 400 mg/day for 6 weeks, with benefits seen after just 2 weeks of treatment. This benefit was not seen with shorter-term administration (<2 weeks).
How Do They Affect Mood?
Modafinil has not been shown to have an effect on mood. It is, however, considered to be a cognitive enhancer and can be used for the treatment of ADHD, narcolepsy, and as a study aid.
Armodafinil does not have a significant effect on mood either. However, it is considered to be better than modafinil in treating ADHD since it does not cause blockage of the dopamine transporter (and hence the dopaminergic system) like modafinil.
This reduces the risk of side effects such as depressive mood that is caused by systemic blockade of dopamine transporters in patients with attention deficit hyperactivity disorder (ADHD).
Do They Cause Weight Loss?
Modafinil has never been shown to cause weight loss unless it is administered concomitantly with other medications that are known for causing weight loss. It can potentially improve weight loss caused by other medications through an increase in wakefulness.
Weight loss caused by modafinil is unlikely to be caused by appetite suppression; rather, it is more likely to be caused by a reduction in the overall time spent eating due to increased wakefulness and enhanced focus.
Armodafinil has been associated with weight loss, possibly due to an increase in energy expenditure. However, further studies are required before a definite conclusion can be drawn.
What are the Side Effects of Modafinil & Armodafinil?
Modafinil is safe at recommended doses and when used as directed. In a review of studies between 2002 and 2006, modafinil was found to be well-tolerated in a large proportion of patients with military service (n=229).
The most common side effects observed were nausea, headache, dizziness and insomnia. Most side effects were mild to moderate in severity. Within studies conducted with modafinil, the most common adverse drug reactions reported were nausea (29% - 53%), headache (24% - 43%), dizziness (21% - 29%), dyspepsia (18% - 24%) and insomnia (17% - 27%).
When compared to placebo, treatment with modafinil resulted in improvements or no change in several symptoms associated with narcolepsies such as excessive daytime sleepiness or fatigue; however, no improvement was seen on psychomotor performance tasks.
On the other hand, treatment with modafinil significantly improved psychological and physiological measures of sleepiness and fatigue compared to placebo.
Armodafinil was associated with similar side effects in clinical studies. The most common adverse drug reactions reported included nausea (50% - 100%), headache (42% - 80%), insomnia (30% - 60%) and dizziness (25% - 50%).
Other common adverse events, not seen with modafinil, include dry mouth, daytime sleepiness, fatigue and feeling jittery.
Armodafinil is not known to have any interactions or contraindications with other medications. It is generally well tolerated when used at therapeutically effective doses for longer durations than 6 weeks.
In some situations i.e., in patients receiving a monoamine oxidase inhibitor (MAOI) or an SSRI medication such as citalopram or fluoxetine within 14 days of starting armodafinil, there has been evidence of lower serum levels of the drug while taking these medications concomitantly.
Modafinil or Armodafinil: Which is Better?
There has been no head-to-head comparison between modafinil and armodafinil in clinical studies. Similarly, there is no information available on the bioavailability of armodafinil on the official manufacturers' website.
Preliminary pharmacokinetic data suggest that the bioavailability of armodafinil is similar to that of modafinil and better than that of D-amphetamine. The bioavailability of armodafinil is not affected by food and is independent of the patient's gender or age.
Therefore, if one was to compare modafinil with armodafinil, most scientific data available suggests that armodafinil would be the better alternative.
However, it should be noted that there are no head-to-head comparisons between the two medications because armodafinil was only approved by the FDA in 2007 while modafinil has been around since 1998. Since armodafinil would not have been compared to modafinil in any studies, it cannot be said for sure which one is better.
Long-Term Use & Other Concerns
A long-term safety study of modafinil (300 mg/day to 400 mg/day) showed that treatment for as many as 4 years was well tolerated without any evidence of tolerance or other adverse effects up to 1 year after stopping treatment with this compound.
In clinical studies, armodafinil was well tolerated at recommended doses for up to 2 years. It is not known what replacement dose or schedule would result in decreased efficacy at this time.
Long-term data indicate that modafinil has little or no evidence of carcinogenic potential, either by inhalation exposure or by ingestion.
Long-term studies in humans have shown that modafinil has a minimal impact on sleep architecture and no significant impact on circadian rhythmicity.
While there is no conclusive evidence of any long-term effects of modafinil, based on animal studies there is a concern about the possible risk of dependence associated with chronic regular use of this drug.
The exact mechanism of how modafinil causes dependence remains unknown but studies suggest that it causes downregulation of dopamine transporters in the brain, which results in dependence on modafinil.
Regular use of modafinil can cause tolerance, which means that more of the drug is required to achieve the same effect after prolonged use. This could potentially cause a buildup of the drug in the system and lead to withdrawal symptoms when it is stopped after long-term use.
However, there has never been any evidence found suggesting that modafinil causes physical or psychological dependence in humans. It may only be beneficial for short-term use so as to avoid any possible side effects associated with long-term regular use.
Armodafinil is not known to cause dependence or tolerance; however, because it is closely related to modafinil there has been no study done regarding this phenomenon. It is not recommended for long-term use and can cause rebound insomnia and anxiety in patients who stop taking it.
Long-term safety data is not available for armodafinil. However, it should be noted that there is no evidence to suggest that armodafinil causes dependence either.
Modafinil is not expected to cause any withdrawal symptoms upon abrupt discontinuation of the drug. However, some patients have reported symptoms such as headache, nausea, anxiety, and gastrointestinal upset when stopping modafinil.
In contrast, armodafinil has been shown to cause rebound insomnia and anxiety in patients who stop taking the medication abruptly after continuous usage over an extended period of time (over 2 years). It does not affect circadian rhythmicity or sleep architecture.
It also has a minimal effect on alertness during sleep and has a minimal or no effect on working memory. Modafinil has a lower abuse potential than other psychostimulants with similar effects like methylphenidate due to its relatively slow onset of action and longer half-life.
Modafinil and armodafinil are both well-tolerated, but long-term safety data for either medication is lacking due to their relatively recent FDA approval in 1998 and 2007 respectively.
It cannot be said with confidence which of these two drugs would be safer, or better, overall.
Modafinil is an FDA-approved drug for the treatment of narcolepsy and ADHD. It has been traditionally used to treat shift work disorders but is also being used as a performance enhancer and study aid.
Armodafinil is a drug under development by Cephalon. It has been shown to cause significant changes on cognitive function in healthy young and older subjects.
It has also been shown to increase energy expenditure, improve weight loss and reduce fatigue in narcoleptic patients. However, it is not known to cause any significant side effects.
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135062/ (Armodafinil versus Modafinil in Patients of Excessive Sleepiness Associated with Shift Work Sleep Disorder: A Randomized Double Blind Multicentric Clinical Trial)
- https://pubmed.ncbi.nlm.nih.gov/19663523/ (Armodafinil and modafinil half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies)
- https://pubmed.ncbi.nlm.nih.gov/26923035/ (Effects of Modafinil and Armodafinil in Patients With Obstructive Sleep Apnea: A Meta-analysis of Randomized Controlled Trials)