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That Wacky Modafinil

Hammilton

Hammilton

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Sep 2, 2008
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How would you classify modafinil?

It binds to DAT, increases MA levels, has odd H3 effects.

There have been some preclinical studies of potential wakefulness-inducing treatments that work biochemically by inhibiting the histamine H3 receptor in the brain. However, modafinil has behavioral effects even in mice whose H3 receptor is genetically knocked out (6). It is possible that modafinil is working on the hypocretin system (7), a unique peptide neurotransmitter system that is abnormal in narcolepsy but is unlikely to be a key player in the biochemical mechanism of bipolar depression. Therefore, one could think of modafinil as a nonspecific or symptomatic treatment of bipolar depression.
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hypocretin? Never even heard of it until now. Oh, it's orexin.

from wiki:

Pharmacology

The exact mechanism of action of Modafinil is unclear, although numerous in vitro studies have shown it to increase the levels of various monoamines, namely; dopamine in the striatum and nucleus accumbens,[54][55] noradrenalin in the hypothalamus and ventrolateral preoptic nucleus,[56][57] and serotonin in the amygdala and frontal cortex.[58] While the co-administration of a dopamine antagonist is known to decrease the stimulant effect of amphetamine, it does not negate the wakefulness-promoting actions of modafinil. Modafinil activates glutamatergic circuits while inhibiting GABAergic neurotransmission. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects.

The central stimulating effect of modafinil shows dose and time-related features. The effect tends to be enhanced by chlorination but reduced by methylation. Modafinil blocks the reuptake of norepinephrine by the noradrenergic terminals on sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.

Modafinil has a binding coefficient (Ki) of about 4,000 nmol/L for the dopamine reuptake transporter, and in excess of 10,000 nmol/L for the norepinephrine reuptake transporter.

A newly proposed mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas, and excite histaminergic tuberomammillary neurons increasing histamine levels there. There are two receptors for hypocretins, namely hcrt1 and hcrt2. Animal studies have shown that animals with defective orexin systems show signs and symptoms similar to narcolepsy. Modafinil seems to activate these orexin neurons thus promoting wakefulness. However, a study of genetically modified dogs lacking orexin receptors showed that modafinil still promoted wakefulness in these animals, suggesting that orexin activation is not required for the effects of modafinil.

It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine and norepinephrine reuptake, as well as orexin activation.

It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans.[59]

Armodafinil a single R-enantiomer of modafinil was approved by the FDA for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome and shift work sleep disorder.
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It seems to not be recreational, but all of mechanisms seem to scream recreational. So why not?

I've taken it two days now (at 175, tommorow I'll go to 200 where I was supposed to start, but better safe than sorry- I was up until 3am last night), and I don't know that I could distinguish it from a low dose of amphetamine. Definitely not like a DARI, which even at low doses I experienced euphoria, but with amphetamine I never did. I don't have any euphoria, but it is still useful.

It's probably the most mentally boosting drug I've ever used.




Also, I've seen some 'modafinil analogues' of phenyltropanes made that were insanely potent; have similar things been tried for regular PEAs or is the ethylamine to short to stick the sulfur into?
 
That DAT affinity is quite low, so at "wakefullness promoting" doses there is little going on in terms of binding to the DAT.

The stuff used to give me nasty headaches after 300mg's.
 
I took quite a bit of this stuff last year when my shrink Rx'd it for me. I was always dead tired.
The first few days it was ok,thinking was cool, then up the anty and the bottle was gone
 
It seems to not be recreational, but all of mechanisms seem to scream recreational. So why not?
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First, because none of those mechanisms completely explains modafinils action completely and all of them seem to contribute only to a very small degree. As Negrogesic elaborated, the affinities are somehow low with most targets.

It's just not "recreational" (how would you define the term?) because it doesn't do anything else than keeping you awake. There IS no euphoria, no increased sociability, no increased libido. None of the fun stuff that amphetamines are producing.

And additionally, as Negrogesic pointed out, if you go too far (IIRC 200 mg are the recommended dose, not 300) than you will only get headaches and other sideeffects. It sounds like the "perfect drug" (if such a thing even exists): It does what it is supposed to do but nothing else. How much else drugs are like this? Especially in the psychoactive field...

I remember to have read that it even takes some days of intake to develop its full activity. So, the abuse liability must be extremely low. It doesn't help to snort it. Has anybody here ever read about injecting modafinil?

Peace! Murphy
 
I've tried the indian brand modalert for the past few weeks, and i can't say i noticed it help my day time sleepiness at all.
the first time it seemed to help, but that may have been placebo.
but now it doesn't seem to do much at all at the 200mg does :(

which is strange because most users comments are quite positive about it, so it makes me think maybe i've been given sugar pills...

im on ssri's if it makes a difference.

edit: murphy i just read what you said about it taking a while to develop full activity, i wonder if that's my problem?
i don't want to take this everyday, just on tired days like the start and the end of a week.
 
Mr TIMO said:
edit: murphy i just read what you said about it taking a while to develop full activity, i wonder if that's my problem?
i don't want to take this everyday, just on tired days like the start and the end of a week.
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I'm very sorry that I can not back up this with a reference but I'm quite convinced that you have to take it regularly for at least 1-2 weeks to feel the full effects. Taking it just occasionally (like it would be possible with amphetamine or methylphenidate, just to mention 2 examples) won't help.
 
IMO its only difference from a low dose of prescription amphetamine is little to no desire to keep re-dosing.

During the last few years I sold commercial real estate, a lot of people I knew took it to work long hours.

It helps me within 1.5 hours of the first dose. Most friends who tried it reported the same. (These were high stress environments where we had worked all day and were attending night meetings with investors out of town.)
 
I honestly admit that I may have confused something here... I can't find any hint that modafinil needs some time to fully develop its effects and until nobody else does so, I take my statement back. I have no idea how fast modafinil acts...

Sorry!
 
The doctors who prescribed it both said it took time also. I think the manufacturer's reps stretch that point to doctors to make it sound like an "anti-depressant". I think the info that came with the package said the same thing.
 
MurphyClox said:
I honestly admit that I may have confused something here... I can't find any hint that modafinil needs some time to fully develop its effects and until nobody else does so, I take my statement back. I have no idea how fast modafinil acts...

Sorry!
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I noticed strong effect within 1.5 hours of my first dose.

My doc started me out at 200mg right away (though I started at 175 roughly) and I noticed greatly improved thinking clarity. I've not had pure dexamp, but this definitely beats amp or methylphenidate as a nootropic.
 
I am interested to hear how modafinil interacts with your buprenorphine ham? I believe you may be getting some drug-drug related effects here.

I was also prescribed modafinil for excessive day time sleepiness, and found it to be a perfect drug for that condition. However, do not mix it with caffeine as you will find yourself an anxious wreck, and going to the toilet all the time.
 
I actually don't notice any effects. I waited 25 hours before taking my suboxone, and I'd usually have expected to feel quite sedated (on my first day of the modafinil) but instead I was rather awake and not really feeling the effects.

I dunno.

I took a 25mg booster at 4:30 this after noon, and I noticed quite a boost, I'm still feeling it.

What I love about this stuff though is that you don't know you're on a drug really. If you're doing something that requires your concentration, you can't really notice.

Definitely second the caffeine thing. I like mixing a little mountain dew into my sierra mist in the morning, maybe 1/8th of the glass is md the other 7/8th mist. I was sweating and anxious. Yuck.
 
I've tried the indian brand modalert for the past few weeks, and i can't say i noticed it help my day time sleepiness at all.
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Unfortunately, modafinil may be one of the only true examples of a generic being vastly inferior to the brand-name formulation. The interesting thing about modafinil is that it is absolutely insoluble in water and is not very well absorbed by the body unless the pill is formulated in a particular way. The company that designed it, Cephalon has a bunch of obscure patents discussing the "particle size" of recrystalized modafinil in Provigil tablets--apparently the compound is only particularly well-absorbed by the gut if the tablets are made in the special "trade secret" way alluded to in the patent. That's my explanation of why generic modafinil sucks ass. I've tried a whole bunch of it--the real brand is insanely pricey (as a psychiatrist once told me: the only major side effect of modafinil is the large hole it leaves in the wallet)--and it never worked as well the brand. Perhaps try to really crush the shit out of generic modalert tabs in a mortar/pestle and put the powder into regular gelcaps?

Although I'm mainly a dextroamphetamine fan, I've been on it for years, never abused it and it has never let me down or given me any side effects. If you abuse the shit out of dextroamphetamine, you are asking for trouble--and if you have that propensity but still want a decent stimulant, modafinil is an excellent option.
 
Modafinil is great.

I am pretty sensitive to it. I have never taken over 100mg, and that was way too much. Normal dose is 25-50. I have noticed that sometimes doses lower than that seem to actually decrease my concentration.

I have however been afraid to take it recently since i found out it can make your epidermis separate from the dermis in rare cases...sounds terrible.

Low doses of modafinil are quite nice with green tea ime. Coffee is a no. But even decaf makes me jittery...
 
I have however been afraid to take it recently since i found out it can make your epidermis separate from the dermis in rare cases...sounds terrible.
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Zuh? I'm never heard of anyone having all their skin fall off from taking modafinil. Maybe someone had one of those super allergic reactions (called Stevens-Johnsons disorder, or something like that), resulting in severe rash and epidermal necrosis?
 
I was recently prescribed Desoxyn tablets, and at low dosages it has the nootropic like properties of 200mg of modafinil. I took 15mg of the Desoxyn yesterday, and it did not give that nasty zombified "must do something" feeling that I get from 15mg of d-amphetamine. I am prescribed 20mg a day, but in actuality I will probably take 5-15mg, once every ten days (at most). Plus, I really don't think it would be healthy to take such a potent releaser of dopamine everyday, even at the lower dosages.

Also, the Desoxyn is considerably more expensive than even the brand name Provigil. Believe it or not, the Desoxyn was my doctors suggestion (after I told him that I was unhappy that pemoline was no longer available, as it felt it had been more centrally acting than d-amphetamine).

Needless to say, from past experience getting "high" on methamphetamine actually sucks for me so I don't feel any need to abuse/misuse. I may eventually go back to Provigil.
 
Quoting Wiki here:
From the date of initial marketing, December 1998, to January 30, 2007, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) involving adult and pediatric patients.
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If necessary, I can provide some publication on this issue. The reports are rare but confirmed to my knowledge.

@Dunwich: If you have taken modafinil for a longer period and haven't noticed any allergic (skin-)reactions or whatsoever, you should be on the safe side. If those side-effects didn't occur yet, they are very unlikely to occur now.

About the solubility/bioavailability-issue:
What about the prodrug Adrafinil? I guess that a hydroxamic acid is somehow better soluble. Any comments here?

Peace! Murphy
 
MurphyClox said:
@Dunwich: If you have taken modafinil for a longer period and haven't noticed any allergic (skin-)reactions or whatsoever, you should be on the safe side. If those side-effects didn't occur yet, they are very unlikely to occur now.
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Yeah i assumed that it already would have happened, but I have gotten some nodular acne type stuff from modafinil. I think. It hasnt happened in a while and the acne was perhaps caused by using l-meth and propylhexadrine inhalers.
 
^^ You might be allergic to the compound then (if the acne is really modafinil-related, which, as you mention, you can't be sure of yet). Modafinil has a sulfa moiety and is metabolized to a sulfonyl compound, which some people can be highly allergic to--they get rashes, hives, etc... Stevens-Johnsons disorder (epidermal necrosis) is the result of a severe, dangerous and potentially life-threatening allergic reaction. Luckily, it is extremely rare, but you hear about it every once and a while, when someone turns out to highly allergic to a given drug. For example, there are cases of severe allergy to the anticonvulsant/mood stabilizer lamotrigine, but I've been on it for years with zero problems. So a handful of allergy cases does not usually indicate that the drug is specifically harmful to the population at large.
 
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