MODAFINIL VS ARMODAFINIL

This is a brief breakdown of some of the differences, similarities and psychopharmacological effects of Modafinil and Armodafinil.

These two commonly used non-stimulant wakefulness promoting agents have for a long time been used for everything from narcolepsy, drowsiness as a result of sleep apnea, shift work disorder, in addition to off label use as adjuncts in depression, as one of the "Go Pills" in the airforce, and even with some use in ADHD. It appears to be a safer alternative to stimulant medications without the same level of abuse potential and dependence, especially when used for purposes other than those mentioned above and for the sole application of wakefulness promotion, with less influence on concentration, impulsivity, motivation and hyperactivity.

In case you're wondering, modafinil and armodafinil are essentially derived from the same molecule. Though whilst, modafinil containing both enantiomers (mirror images of the same compound) appears to have a more potent DAT blockade activity, compared to the right enantiomer (Armodafinil) which is derived from the racemic version being modafinil. Racemic meaning, containing both enantiomers of the same molecule, typically in equal parts (full spectrum chemical structure).

Firstly, modafinil acts quicker and has a slightly more stimulant like effects possibly due to its slightly mood elevating and stimulant-like effects primarily through DAT blockade activity via sodium dependent reuptake into the presynaptic terminals, causing a comparatively weak but likely still signficant mechanism of the inhibition reuptake of dopamine and a signficantly weaker and indirect effect on noradrenaline reuptake.

How that translates into the real world use of the two medications is what's likely the main interest for most people so let's take a closer look at just some of the known mechanisms of these medications, since despite what was once thought about the extent of the compound's psychopharmacology, overtime additional links between it's various direct and indirect mechanisms, as well as additional (albeit seemingly secondary) mechanisms, some of which won't be discussed in this brief overview.

During it's first 1-4 hours of the ingestion of modafinil, the majority of the effects experienced is mainly produced by the S-enantiomer of the molecule which has a shorter duration of action. It's metabolized hepatically by 6 different CYP450 enzymes by varying degrees, which in order of most potent activity to least, 2C19 (inhibitor), 3A4 (as both a substrate and a weaker inducer), 1A4 (inducer), 2B6 (mainly as an inhibitor but also a weak inducer). To a far lesser extent, it can have a weak primarily inhibiting effect on 2C9, and lastly basically negligible effect on 3A5 at most therapeutic doses.

By taking modafinil, you're basically also taking armodafinil but to a lesser extent than when used in it's isolated form at therapeutic doses (anywhere from 50 - 400mg) daily depending on the condition being treated, sometimes in decided doses especially at higher doses due to the efficiency of metabolising more than a certain amount of the compound at once). This is especially true when its combined with other medications or herbs that react with the drug, affecting it's metabolism and therefore it's plasma concentrations.

Although armodafinil also has a slower onset of action, it has in return a longer half life and duration when compared to modafinil. Armodafinil typically reaches peak plasma concentrations in 2-4 hours. The exact rate of metabolism is dependent on factors including but not limited to genetic liver CYP450 enzyme variations and renal function.

The effects of armodafinil are only just beginning to peak as the duration of the additional enantiomer is slowly wearing off (this is what makes modafinil different to armodafinil). The onset of action seems to be about half of that of armodafinil, at around 45-60 minutes. With armodafinil, the onset may be delayed for up to 2 hours in some individuals.

Additionally, despite its slower onset and higher relative potency next to its S-enantiomer (strictly in terms of dose efficiency), armodafinil also has a longer duration of action and half life than modafinil (due to its racemic structure containing both enantiomers in one molecule, resulting in a lower dose of the R-enantiomer being ingested).

Naturally, despite modafinil also having armodafinil as part of its composition, when the enantiopure version of the same molecule (armodafinil) is isolated and used at a higher dose, there's an increase in its duration and half life. This gives armodafinil an advantage for patients who require a longer duration of action and the core eugeroic (wakefulness) effects.

Alternatively, modafinil is more suitable when a shorter duration is indicated. As a result of the left enantiomer (found in modafinil) being absent in armodafinil, less effects on mood (which can be good or bad depending on the application) but a more consistent and sustained subjective effect that's correlated and confirmed by the compound's pharmacokinetic properties and graph structure is observed.

It should also be noted that whilst both medications have shown to be effective for significantly long periods of time as seen in a few high quality clinical studies, it's shown that little to no tolerance is built to at least the primary wakefulness promoting effects of the two drugs, which appear to more likely being associated with the histaminergic and anti GABA activity resulting in reduced gaba levels (of at least two sub types (A & B, with less certainty regarding c) seem to take longer to develop in regards with tolerance. The rate at which is takes place varies.

The fairly weak DAT blockade activity of the especially modafinil, leading to increased dopamine levels and possibly increasing focus and concentration. Having said that, this effect seems very mild at best and has little relative binding affinity at typical doses to these sites to produce a significant effect via this particular mechanism.
This also likely contributes to the low addiction liability of the two drugs, with armodafinil showing a slightly higher liability possibly due to its overall potency and less tolerance development compared to the racemic, modafinil, at least based on the subjective experiences commonly reported.

The dependence liability of both drugs is also shown to be very low to low. This is of course relative to other stimulants and does not mean there are negligible effects on either characateristic.
Moreover, there is some partial impact on it's effect on the decrease in glutamate levels (opposite of some of the effects of certain mood stabilizers such as Lamotrigine).

Multiple rat studies examining it's effect on cocaine naive rats, as well as those preferentially self administrating cocaine indicated little to no reinforcing or rewarding effects, with a slightly higher risk for cocaine addicted rats. This effect appears to be significantly weaker in humans, partly due to the doses typically used in medical practice, hence perhaps explaining the negligible addition liability in humans. It's been shown in double placebo controlled trials that that especially at higher doses, modafinil was effective for reducing the number of days of cocaine use in addicted individuals (although those without co-morbid alcohol dependence) and reduced craving.

A discontinued and previously legally used pro drug to modafinil called adrafinil would be metabolized into modafinil with an inconsistent active dose of the active being delivered (similarly to codeine and tramadol), as well as having potentially hepatotoxic effects resulting in it being withdrawn from use as a medicine. Its still sold as a dietary supplement and "nootropic" in some countries and is no longer regulated under the same standards as pharmaceutical medications.

Going off on a tangent to, oxazepam and tamezepam are metabolites of diazepam and therefore will be slowly metabolized from one to the other, with the last metabolite being tamezepam. This likely contributes to most of the hypnotic and furthermore amnesic effects of diazepam, especially when used at higher doses (in pre-operative hospital settings as an example), but also it's retrograde amnesia producing properties which disables the patients from recording the memory of the events taking place throughout the duration of action of each particular drug on it's own, or for when diazepam is used at higher doses than ones typically used for anxiety relief or muscle relaxant purposes.

Because of the more or less, pro drug structure of diazepam, leading to less predictable and/or desired potency of effects, oxazepam and tamezepam, being two of diazepam's active mtabolites, are now widely used for more specific purposes such as isolating the hypnotic effects of temazepam and to a lesser extent oxazepam in a more efficient and predictable way, for when a specific and selective characteristic within each benzodiazepine's relatively unique purpose, duration of effect, half life, onset of action as well as indicated (or typical) use ranging from purely sedative hypnotic effects to when a predominantly anxiolytic effect is desired (amongst many other uses, both indicated and off label).

This selectivity however also magnifies the amnesic properties of the two active drugs, therefore limiting their use mainly as a sleep aid, or in the case of oxazepam, less frequently in lower doses for anxiety. It's use for this purpose is far from ideal though due to its relative amnesic, weak and slow onset of action, despite having one of the shortest half lives amongst other benzodiazepines.

Regardless, diazepam still remains one of the most widely used benzodiazepines in use today, despite being the second benzodiazepine synthesized and many newer and potent ones which although have largely replaced it’s use in anxiety and sleep disorders, reserving it’s more broad characteristics and long half life, making it superior to many others in its class for purposes like alcohol withdrawal (at higher doses), muscle relaxant properties, acute anxiety (at lower doses) or even for tapering off other benzodiazepines due to its longest-in-class half life, lower potency and calculating it’s approximate dose equivalency when switching from a different benzodiazepine.

Also important to note is that each benzodiazepine tends to lean toward a specific selection of typical characteristics. These include as a class sharing certain properties including hypnotic, anxiolytic, anti-epileptic etc. A benzodiazepine like alprazolam despite being signficantly more potent and selective in comparison to diazepam as an anxyiolytic at roughly equivalent doses, will for example produce less muscle relaxant effects than diazepam at lower doses, and have a less likelihood to induce sleep due to not sharing the signficantly hypnotic and amnesic metabolites of diazepam, temazepam and oxazepam.

For example, although different guidelines may vary (in UK, Australia, US), 0.25mg of clonazepam or 0.5mg of alprazolam is roughly equivalent to 5mg of diazepam.

This doesn’t mean that the subjective experience or therapeutic value of "equivalent" doses will be identical, but rather is mostly useful when switching between benzodiazepines in a safe and controlled way.

It also helps to understand and differentiate between different dosage intervals required for each given drug. Similarly, though modafinil is used at doses ranging from 50-400 daily, sometimes in two divided doses, armodafinil which is more potent per mg, is usually only given once per day, at doses ranging from 50-250mg, with 150mg being the more common dose in most applications.