Nootropics researchers may find themselves weighing the pros and cons of adrafinil vs. modafinil. Both are non-amphetamine stimulants that have a strong effect on vigilance and wakefulness, and they have similar mechanisms of action. So, which one may be better suited for your research study?
In this A-Z guide, we’ll outline the similarities and differences between adrafinil and modafinil and explore the precautions that researchers must take when working with either substance. We will outline the main benefits and side effects of both adrafinil and modafinil, before providing our verdict on which you should buy.
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What Is Modafinil?
Modafinil is a prescription medication that is commonly prescribed to treat symptoms associated with sleep disorders like :
- Shift Work Sleep Disorder (SWSD)
- Sleep Apnea (SA)
Modafinil does not treat the sleep disorder itself; it simply acts as a stimulant that increases wakefulness and decreases sense of fatigue, allowing patients to lead a more normal life .
Several studies have also shown that modafinil offers cognitive neuroenhancement in non-sleep-deprived individuals . It is used in real-life situations as a stimulant and performance enhancer. For example:
- It is routinely used by military aviators to stay awake and perform well on long missions .
- It is used by astronauts on the International Space Station (ISS) during periods when sleep is disturbed .
- There is substantial evidence that many non-sleep-deprived individuals use modafinil “off-prescription” to enable them to work longer hours or function at a higher level in their daily lives .
In sum, modafinil is much more than just a stimulant—it is also a performance enhancer.
Pharmacology of modafinil
How does modafinil work? Scientists are not exactly sure, but there are three main theories.
- Blocking norepinephrine reuptake: Norepinephrine is one of the neurotransmitters involved in getting the body ready for action. More norepinephrine equals being more alert. Scientists believe that modafinil works in part by blocking the reuptake of norepinephrine, leaving it in the synapses of the nerve cells for longer and upregulating its effect .
- Blocking dopamine reuptake: Modafinil also acts as a weak dopamine reuptake inhibitor, resulting in an increase of dopamine in nerve cell synapses. Dopamine has a strong effect on mood, and this is one of the main ways that researchers believe modafinil to influence mood .
- Regulating other neurotransmitters involved in wakefulness: Modafinil has a number of other effects on neurotransmitters. It influences everything from histamine, GABA, orexin, and serotonin—each of which plays a role in regulating wakefulness and sleep cycles. It is thought that modafinil has several indirect effects on these neurotransmitters, which together promote vigilance and alertness .
Again, modafinil’s precise mechanism of action is not yet fully understood. But we do know that modafinil has a pronounced effect on wakefulness, mood, and cognition.
Modafinil Side Effects and Safety
What about modafinil side effects? Is modafinil safe?
The research available is overwhelmingly consistent in finding that modafinil is generally well-tolerated by test subjects [7, 8]. It has been approved by numerous drug regulators worldwide, including the United States Food and Drug Administration (“US FDA”), to treat symptoms of narcolepsy and other sleep-wake disorders.
Clinical trials have linked modafinil to the following side effects :
- Decreased appetite
While some test subjects have experienced these side effects, they are relatively uncommon and typically mild in terms of their severity. In a review of modafinil’s neurochemical actions and effects on cognition, Minzenberg and Carter concluded that “modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse” .
While research involving modafinil is ongoing, its side effects and safety profile suggest that it is an excellent candidate for nootropics research.
Having reviewed modafinil’s main benefits and side effects, we’ll now turn our attention to adrafinil.
What Is Adrafinil?
Adrafinil is a prodrug of modafinil and is metabolized in the liver when ingested. It was first synthesized in France by Louis Lafon Laboratories in 1974, and released as the prescription drug “Olmifon” in 1985. Olmifon’s main use was to increase vigilance in elderly patients .
Human trials have observed that adrafinil produces the following effects in elderly patients [11, 12]:
- Increased vigilance
- Sense of alertness
- Longer attention span
- Improved mood
- Higher levels of energy
- Reduced anxiety levels
In 2011, Cephalon France discontinued the manufacture of Olmifon following the French medical authorities' decision to revoke the drug’s marketing approval. A number of drug manufacturers and compounding pharmacies currently produce adrafinil as a research chemical.
Pharmacology of adrafinil
How does Adrafinil work?
Adrafinil’s exact mechanism of action is not yet fully understood. However, the primary hypothesis is that modafinil is likely responsible for the bulk of adrafinil’s effects .
As a prodrug of modafinil, adrafinil exhibits a robust effect on catecholaminergic systems (catecholamines) and neurochemical actions in the brain such as gamma amino-butyric acid glutamate, histamine, orexin, and serotonin. Research involving elderly subjects has shown that this action helps improve cognitive processes such as working and episodic memory, mood, and thinking [11, 12].
We’ll now address adrafinil’s side effects and safety.
Adrafinil Side Effects and Safety
Is adrafinil safe?
Research on human subjects to date suggests that adrafinil is generally well-tolerated and safe . Most clinical trials have involved doses of 900 mg/d, and the standard dose of Olmifon administered to elderly patients was 2-4 tablets per day (600 – 1,200 mg/d). According to the Summary of Product Characteristics for Olmifon (“Olmifon SmPC”), published by Cephalon France in 2011, the main side effects observed with adrafinil are as follows :
- Inner tension/mood swings/psychic excitement
As a liver-metabolized prodrug of modafinil, there is concern that prolonged use of adrafinil can cause elevated liver enzyme levels. The Olmifon SmPC states that patients with severe hepatic or renal impairment were to be prescribed a lower dose of 300-600 mg/d .
Unlike modafinil, which has several long-term trials showing that it can be safely taken for three years without major side effects , no such long-term data exists regarding adrafinil. This highlights an area where further research may be warranted.
Adrafinil vs. Modafinil | Similarities
Both adrafinil and modafinil are wakefulness-promoting substances with proven efficacy for improving vigilance. However, the literature on modafinil is far more extensive and there are a number of key areas where research with adrafinil may prove advantageous. Here’s a review of the similarities between adrafinil and modafinil.
Several studies have found that modafinil can improve memory speed and accuracy [14, 15]. It seems to improve working memory tasks , recognition of visual patterns , episodic memory [16,] and reduces error rates .
Early animal research involving adrafinil suggests that it produces significant improvements in learning when administered to aged canines . Several human studies have likewise shown that adrafinil can improve the memory and recall of elderly human subjects [11, 12].
One human clinical trial looked at the effect of adrafinil on memory, finding that it led to significantly better scores on a recall task compared to a placebo-controlled group . Participants also had better scores on forgetfulness measures . Another large study of over 500 patients reinforced these findings: patients treated with adrafinil saw significant improvements on a memory task [19 as 18 cited in 10].
Research on sleep-deprived individuals has found that modafinil increases focus to non-sleep-deprived levels , while separate studies have found that modafinil improves attention performance even in non-sleep-deprived individuals [9, 21, 22].
There is evidence that adrafinil offers similar effects . Research on elderly adults found that taking three adrafinil tablets a day (990 mg) for 90 days led to significant increases in attention and vigilance . This is reinforced by another small study of participants aged 45 to 88 .
Enhanced cognitive function
A number of studies have found that modafinil can improve various aspects of cognitive functioning including spatial planning, , reaction time , planning , decision-making , and visual processing .
Similarly, the few published human studies on adrafinil suggest that it boosts cognitive function in elderly populations. Older, healthy adults that were given adrafinil for three months performed significantly better on measures of intellect, concentration, and perceptual acuity than those given a placebo .
Both modafinil and adrafinil have shown efficacy in reducing fatigue. Modafinil has been found to counter fatigue in patients with multiple sclerosis , patients undergoing chemotherapy , and subjects with depression . Further studies found that it significantly reduced fatigue in sleep-deprived military personnel .
Research on adrafinil has also found that elderly participants administered adrafinil report feeling less fatigued than a placebo-controlled group .
Improved mood and motivation
One of the potential benefits of both modafinil and adrafinil is that both offer a boost in mood and motivation.
Several studies have found that modafinil produces feelings of well-being [28, 29]. Researchers have found that modafinil helps subjects take more pleasure in their work .
Similarly, researchers have found that subjects treated with adrafinil report feeling happier than those in a placebo group and report improvement in depression and anxiety symptoms. Nurses observed patients on adrafinil and rated them as less depressed, less irritable, more patient, and more sociable than their placebo-controlled counterparts .
Needless to say, modafinil and adrafinil share several key benefits. The two compounds are largely similar in their function and both have potential to produce significant cognitive benefits and improvements to mood in subjects.
Modafinil vs. Adrafinil | Differences
While they are largely similar in their effects, there are some important differences between modafinil and adrafinil. Understanding these differences can help researchers decide on a study protocol.
Modafinil is markedly more potent than adrafinil in the context of treating sleep-wake disorders. Narcolepsy patients are typically prescribed just 200 mg of modafinil per day , much less than the 600-1,200 mg/d of Olmifon prescribed to elderly patients to promote vigilance during the time when this drug was available .
Modafinil is more specific than adrafinil in its action on the body, which may be why it is believed to have a more favorable safety profile. Adrafinil has been linked to a number of side effects such as gastralgia and oral-facial dyskinesias , which are not associated with modafinil . Concerns regarding adrafinil’s benefit-to-risk ratio informed the French medical authorities’ decision to withdraw marketing permission for Olmifon in 2011.
Onset and half-life
As adrafinil is a liver-metabolized prodrug of modafinil, it has a longer onset period than modafinil. According to the Olmifon SmPC, the drug took 0,90 ± 0,2 h to reach maximum plasma concentration in the body .
By comparison, modafinil (which is also liver-metabolized) has a much shorter onset period. For example, patients with SWSD are advised to take 200 mg of modafinil roughly 60 minutes before starting their shift .
When comparing modafinil vs. adrafinil, one of the most striking differences is in the volume of research available for each compound. Modafinil has been far more widely studied than adrafinil and, as a US FDA-approved drug, has a far greater body of research behind it.
What Nootropic Should You Buy?
Researchers curious about the best research chemical to buy for their next experiment should consider a range of factors before making a decision. There are clearly a number of areas where data regarding adrafinil’s effectiveness is lacking, not least of which is its effects in non-elderly populations. This suggests that there are more potential opportunities for researchers who want to run studies with this research chemical.
On the other hand, modafinil appears to have a less concerning safety profile than adrafinil. While relatively fewer research opportunities exist with modafinil, the difficulty of designing and running a safe trial is arguably less than with adrafinil.
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Adrafinil vs. Modafinil | Verdict
Adrafinil and modafinil are vigilance-promoting compounds that have demonstrated high efficacy in treating symptoms associated with sleep-wake disorders. To date, clinical trials conducted with adrafinil have focused predominantly on vigilance-enhancement in elderly patients, while trials involving modafinil have focused mainly on narcolepsy.
This suggests that both compounds are effective in slightly different circumstances and illuminate areas where researchers can design and conduct further investigations. For instance, further research into adrafinil’s action in non-elderly populations seems warranted, while research into modafinil’s action as a vigilance-enhancer could prove similarly fruitful.