# Modafinil and Modafinil Explored



## Arnold (Aug 26, 2019)

*Modafinil and Modafinil Explored*

*Modafinil*

I first read about modafinil in Muscle Media 2000, where it was claimed by Charles Poliquin to be in heavy use by sprinters to improve reaction time off the starting gun, and by Dan Duchaine to be a favorite of life extension enthusiasts (?geezers,? I believe he called them) seeking to stave off cognitive decline.

Duchaine, being the swell chap that he was, graciously provided the addresses for overseas life extension companies who were more than willing to ship modafinil to America. I?m sure you can see where this story is going?

But unfortunately, I can?t give much of a personal review of this compound, because I used it simultaneously with Hydergene and Piracetam. So despite its recent emergence as the drug c?l?bre for the ostensible biohacker crowd, it?s been widely circulated in the better-performance-through-chemistry circle for a very long time. Unfortunately, it?s now a Schedule IV drug, which puts it in the same legal category as certain prescription narcotics like tramadol and phenobarbital.

Forgetting its off-putting narcotic-ey legal status, modafinil is still available with a prescription for conditions that require a wakefulness agent (eugeroic) ? we?re talking about narcolepsy, shift work sleep disorder, etc?If you?re tired all day, this is one of the potential drugs that can be prescribed. This, of course, assumes that you can fall asleep and stay asleep, as those conditions generally warrant a sleep aid instead of a wakefulness aid.

Various branches of The United States Military regularly prescribe (or have prescribed) amphetamine to soldiers (the Air Force?s infamous ?go pills? come to mind), as do many others around the world. Many have looked into modafinil as an alternative to the more traditional amphetamines?and that includes not only the U.S., but also the U.K., Canada, France, and India. Starting in 2012, the United States Air Force began replacing their amphetamine-based pills with modafinil.

I?m not aware of any statistics that confirm how many people are using it for narcolepsy, but in the so-called biohacker community it?s become very popular over the past few years. In terms of the athletic community, it?s banned by most sporting organizations and easy enough to test for (although it may not appear on most organizations standard battery). In the former community, it?s thought to be a cognitive enhancer, and I think if we take a look at its mechanism of action and the currently available research, I believe that?s a well-supported position.

Setting aside issues of legality, what follows is not meant to be an all-inclusive tract on modafinil, but rather a crash course for the uninitiated.

Like many other medications, modafinil is thought to operate by at least one primary mechanism and potentially numerous secondary mechanisms. It?s generally accepted that modafinil exerts the majority of its effects through inhibiting dopamine reuptake. Based on what I?m seeing in the clinical data, this seems to be the most sensible locus of activity.

Dopamine is a neurotransmitter, and when reuptake is inhibited, and more is circulating, neurotransmitter activity is enhanced (and here, usually cognition). This is highly intuitive, even if you?re not using modafinil ? increase the circulating levels of neurotransmitters (the chemical messengers used by the brain), and you?re likely to increase cognitive (thinking) ability.

As you may have guessed, dopamine reuptake transmitters are used clinically for the treatment of cognitive disorders, such as attention-deficit hyperactivity disorder (ADHD), but also for conditions like narcolepsy (the latter we see with modafinil?s strict prescription regulations, but off-label many enthusiasts find that it helps the former). The broad category of dopamine reuptake transmitters might also have use as an adjunct treatment for obesity and binge eating disorder (the primary treatment being to just put the fork down), for their appetite suppressant effects. With regards to modafinil, many users report a stimulatory effect that seems to curb their appetite, regardless of whether that?s the intended use.

Although the jury is still out on the definitive cause for depression, dopamine is certainly part of the picture, and as a result dopamine reuptake transmitters are sometimes prescribed as anti-depressants and other mood disorders.

The most commonly used description of modafinil is that it?s a ?selective, relatively weak, atypical dopamine reuptake inhibitor.? But it?s important to note that dopamine doesn?t operate in a vacuum within the human (or animal) body, and neither does modafinil ? it clearly exerts effects on histamine, norepinephrine, and serotonin.

Pharmacologically, modafinil has a really unique profile, and I?d be hard pressed to identify another drug that has the same pharmacokinetic and pharmacological effects throughout the same spectrum and via the same mechanism of action (well, assuming we aren?t talking about drugs on the same branch of that family tree, such as armodafinil (sadly also a Schedule IV drug) and adrafinil (which appears to be widely available and not specifically scheduled at the moment).

Despite its effects on dopamine and serotonin (brain chemicals that make us feel good), modafinil doesn?t seem to have much addiction potential ? and although it?s been more difficult to obtain in recent years, compared to when I first used it, I suspect we?ll be talking about it for a long time to come.

*References:*
?	Robertson P, Hellriegel ET (2003). ?Clinical pharmacokinetic profile of modafinil?. Clinical Pharmacokinetics. 42 (2): 123?37. doi:10.2165/00003088-200342020-00002. PMID 12537513.
?	Battleday RM, Brem AK (Nov 2015). ?Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review?. European Neuropsychopharmacology. 25 (11): 1865?81. doi:10.1016/j.euroneuro.2015.07.028. PMID 26381811.
?	Menza MA, Kaufman KR, Castellanos A (May 2000). ?Modafinil augmentation of antidepressant treatment in depression?. The Journal of Clinical Psychiatry. 61 (5): 378?81. doi:10.4088/JCP.v61n0510. PMID 10847314.
?	Taylor GP, Jr; Keys RE (December 1, 2003). ?Modafinil and management of aircrew fatigue?. United States Department of the Air Force. Retrieved September 18, 2009.
?	Mitler MM, Harsh J, Hirshkowitz M, Guilleminault C (2000). ?Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy?. Sleep Med. 1 (3): 231?243. doi:10.1016/s1389-9457(00)00031-9. PMID 10828434.



*Adrafinil *

Adrafinil is a drug originally developed to improve attention, mood, and (primarily) wakefulness. As you might expect, those are mental attributes that most people would like to have more of ? but especially nootropic enthusiasts, who seek to improve brain function through pharmaceutical means.

Adrafinil is also considered a mild stimulant, although I?m far more comfortable with the previously stated verbiage of ?improving wakefulness? rather than saying it?s an actual stimulant. Frankly it just what people generally mean when they talk about stimulants ? i.e. a rapid onset of effects and an unmistakable ?feel? of being stimulated (think caffeine). It?s also not as potent of a stimulant as modafinil or any of the more common preworkout chemicals. But as with other nootropics (piracetam, etc?) it has found it?s way into the hands of both athletes and bodybuilders.

In fact, in much of the nootropic crowd, adrafinil is considered mainly a prodrug to modafinil [Link to my modafinil article here], or modafinil?s little brother. But in fact, adrafinil was discovered in 1974, and it wasn?t until two years later that modafinil was identified and isolated as the primary active metabolite. In other words, adrafinil is the substrate (starting material) from which modafinil (the metabolite) is created within the body. As a result, adrafinil (under the trade name Olmifon) was on the market by 1984, two years before modafinil. However, as of 2011, adrafinil was discontinued by the company who originally brought it to the market (although they still offer modafinil).

However, while modafinil is a Schedule IV drug in the United States, adrafinil remains unscheduled and widely available online. As a result, while the former might be the first choice for many, the latter is far easier to obtain. To be sure, adrafinil is less potent than modafinil, but it would be a mistake to believe that adrafinil is not worthwhile in it?s own right, notwithstanding its reputation of being modafinil?s little brother.

Initially it was assumed that adrafinil was simply a ?1-adrenergic receptor agonists. This was primarily an inductive (not deductive) conclusion reached as a result of ?1-adrenergic receptor antagonists blocking the effect of adrafinil. However, there is otherwise limited evidence to support this theory. I?m not convinced that it has zero activity at this receptor, but far more robust data indicates that it is an atypical blocker of the dopamine transporter and a dopamine reuptake inhibitor (albeit with weak action and ?feel? compared to many others in the same category). and this action may explain some or all of its pharmacological effects, similarly to modafinil (which again, is a metabolite of adrafinil and which itself is the substrate for modafinil acid and modafinil sulfone).

Adrafinil has a very brief biological half life (one hour) but when it converts to modafinil in the body, that metabolite has a 12-15 hour half life. So the effects of multiple doses will ultimately build up in the body ? an important fact when we are talking about a drug that?s 80% bioavailable and primarily metabolized by the liver. Some experienced users claim that a 3x/week or every other day strategy works best, with a divided dose of 300-600mgs taken upon waking and again at noon. Personally, I think based on the studies I?ve seen, I believe that ideal dosing may fall into that range, but I?d probably want to have a more consistent blood level and opt for 600mgs upon waking and 300mgs at noon, daily, for no more than 2-3 months (depending on bloodwork and liver function).

I think that people tend to really miss the boat by eschewing adrafinil just because it?s not modafinil, or because it doesn?t have the rapid onset of traditional stimulants, and it doesn?t have the near immediate boost in concentration that people (unrealistically) expect from cognition-boosting pills.

Remember though, adrafinil is banned by the World Anti-Doping Agency, and is easily detected. So while I know my fair share of athletes and bodybuilders who use the stuff, it?s not an option if you?re competing in drug-tested sports.


*References:*
?	Milgram, Norton (1999). ?Adrafinil: A Novel Vigilance Promoting Agent?. CNS Drug Reviews. 5 (3): 193?212.
?	Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH (May 2009). ?Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil?. The Journal of Pharmacology and Experimental Therapeutics. 329 (2): 738?46.
?	Dowling G, Kavanagh PV, Talbot B, O?Brien J, Hessman G, McLaughlin G, Twamley B, Brandt SD. Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940 and CRL-40,941 in the GC injector: formation of 1,1,2,2-tetraphenylethane and its tetra fluoro analog. Drug Test Anal. 2017 Mar;9(3):518-528.
?	Deventer K, Roels K, Delbeke FT, Van Eenoo P.Prevalence of legal and illegal stimulating agents in sports. Anal Bioanal Chem. 2011 Aug;401(2):421-32. doi: 10.1007/s00216-011-4863-0. Epub 2011 Apr 9.
?	Rao RN, Shinde DD, Talluri MV, Agawane SB. LC-ESI-MS determination and pharmacokinetics of adrafinil in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Sep 15;873(1):119-23.
?	Siwak CT, Callahan H, Milgram NW. Adrafinil: effects on behavior and cognition in aged canines. Prog Neuropsychopharmacol Biol Psychiatry. 2000 Jul;24(5):709-26.
?	Siwak CT, Gruet P, Woehrl? F, Muggenburg BA, Murphey HL, Milgram NW.Comparison of the effects of adrafinil, propentofylline, and nicergoline on behavior in aged dogs.Am J Vet Res. 2000 Nov;61(11):1410-4.


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