That Wacky Modafinil

[P A]

D2High occupancy isn't particularly relevant to healthy humans in vivo, as evidenced by the apparent lack of D2 agonist-associated [side]effects during the clinical trials. Rule of thumb: if none of the patients are vomiting, twitching, or hallucinating, it's probably not a functional D2 agonist, the hallucinations being particularly relevant in disorders like schizophrenia, which, interestingly enough, Provigil is being used to treat. And the facts that the molecule happens to both inhibit reuptake and weakly displace cocaine at the transporter don't predicate lumping modafinil's mechanism in with the rest of the classical pyshcostimulants as though the real-world clinical profile has lost relevance. None of the mechanisms described above do anything to explain modafinil's more selective behavioral properties and negligible incidence of side effects as compared to other contemporary catecholamine transporter blockers and substrates.

Directly increasing conductance across the membrane or amplifying presynaptic Na/Ca influx (by way of some of the mechanisms I mentioned in my other post) could theoretically allow for elevated displacement of transporter ligands and transient, voltage-dependent inhibition of monoamine reuptake (and stimulation of electrically evoked release) resembling that of the conventional stimulants, minus the stereotypy, euphoria, and locomotor effects. This theoretical RI/release mechanism would be similar to that of acetylcarnitine (which modestly releases dopamine and acetylcholine through selective nicotinic modulation/agonism) and hyperforin (broad-spectrum reuptake inhibition via presynaptic TRP6 activation on GABA, glutamate, 5-HT, DA, and NE neurons) on their target neurotransmitter systems. Regionally selective exocytosis of GABA neuron gap junctions would allow for enhanced H3 receptor binding alongside some of the low-level 'amphetamine-like' effects observed in higher doses.

On the other hand, modafinil could simply be exploiting an as-yet undiscovered chemical discrepancy, either by binding exclusively to an allosteric site on the transporter or acting on a regionally localized subunit. But I doubt it, if only because the "enhanced coupling" theory seems much more promising as a novel explanation for novel drug properties.

 

[Heuristic]

One issue: I don't agree with H that people tend to respond to stimulants markedly differently depending on whether they have AD(H)D or not. Due to modafinil's unique mechanism of action, there might be some clearer difference.

ebola

Well, and I apologize for not including references in here, most of what I've read concerning cognitive enhancers has found, as one would expect, much more dramatic differences for people who have ADD/ADHD than for normal subjects. That is, improvement after dose for people with ADD/ADHD is much more dramatic than improvement after dose for normal subjects.

For people with high IQs and not suffering from ADD/ADHD, the effect of these medications was especially small.

Not really all that surprising, is it? My only caveat would be that these medications are effective at restoring a substantial amount of function lost due to sleep deprivation.

I also have the sense here that I've misunderstood part of what you're saying. Could you elaborate?

 

[PsychedelicPeptide]

Well the important thing for the D2 paper that I saw is the large discrepancy between the two modafinil isomers, where the R form has activity but S virtually nothing. BUT their data is a bit suspicious since they say so many compounds stimulate D2... I didn't read the article but looking back again on it I'm not sure we should buy it. You are right about the D2 agonism though I wasn't thinking much about that.

 

[naginnudej]

Does anyone know what the rectal bioavailability of this substance is?

 

[Solipsis]

No but I bet its high, considering the effectiveness of insufflation.

Actually, watch out not to overshoot your target dose because that could be quite uncomfortable.
Intranasal an impressively small dose gets absorbed not only well but hard and fast, letting you easily
achieve the desired effect.
Yes it lasts a little less long but not thát much, plus you could always redose. I like to be able to sleep
without problems after using though. Not that its extremely hard to fall asleep a while after dosing...

So, do you think it undergoes significant first-pass metabolism?

 

[Silverfox]

Intranasal an impressively small dose gets absorbed not only well but hard and fast, letting you easily
achieve the desired effect.

What dose do you insufflate and are you insufflating ground up tablets? My 200mg Modalert tablets weigh 320mg so the effective dose is 62.5%

 

[MurphyClox]

At this point I have to chime in...
Why are you guys snorting modafinil at all? There is no rush of upcoming effects, not even when injecting the drug AFAIK. Bioavailalibity seems to be sufficient. So why the heck putting such stress to your nose mucosa?

Please enlighten me. Thx!


- Murphy

 

[naginnudej]

At this point I have to chime in...
Why are you guys snorting modafinil at all? There is no rush of upcoming effects, not even when injecting the drug AFAIK. Bioavailalibity seems to be sufficient. So why the heck putting such stress to your nose mucosa?

Please enlighten me. Thx!

No but I bet its high, considering the effectiveness of insufflation.

Intranasal an impressively small dose gets absorbed not only well but hard and fast, letting you easily
achieve the desired effect.

There seems to be some merit In Sols post.

So, do you think it undergoes significant first-pass metabolism?

This may not be of much help, but I read these pending patents which [briefly] discuss the matter. Their credibility is for you to decide:

[0028]As noted above, currently available compositions of modafinil are in the form of tablets that are swallowed. Accordingly, modafinil may be formulated for oral administration for hepatic first-pass metabolism wherein the drug is swallowed and passes into the gastrointestinal tract (gut) and then into the liver before entering the systemic circulation. However, preferred routes of administration of modafinil for compositions and methods described herein are those that are likely to provide faster delivery and lower risk of degradation of modafinil than are associated with first-pass metabolism. Such preferred routes of administration of modafinil include, but are not limited to, sublingual, buccal, nasal, intravenous, subcutaneous, intramuscular, topical (including transdermal), and rectal modes of administration. Although delivery directly into the systemic circulation is more preferred than via the gut and liver (hepatic first-pass metabolism), the concentration of modafinil in the systemic circulation must be sufficient to ensure that an effective amount penetrates the blood-brain barrier and is delivered to the brain and CNS, which are the preferred targets of delivery. Administration to the mucosa of the nasal passages or of the mouth is particularly preferred owing to the fact that some of the capillaries underlying the mucosa provide a conduit directly to the circulation of the brain and CNS. Thus, formulations of modafinil for nasal or oral mucosal administration are not only convenient for pm dosing, but may provide the added benefit of requiring a lower concentration per dose owing to the enhanced efficiency of delivery to the brain and CNS.

Read more: http://www.faqs.org/patents/app/20090318559#ixzz0w39VjAbn

 

[ebola?]

Well, and I apologize for not including references in here, most of what I've read concerning cognitive enhancers has found, as one would expect, much more dramatic differences for people who have ADD/ADHD than for normal subjects. That is, improvement after dose for people with ADD/ADHD is much more dramatic than improvement after dose for normal subjects.

I don't think that casual conversation demands references. On second thought, I don't think that we actually disagreed. The cognitive effects of stimulants, namely increased top-down directed linear thought, and according reduced influence of bottom-up novelty on top-down directives, tend to be similar between patients with ADD and without. However, in intelligence tests and perhaps scholastic work, those with problems with distractability benefit more in terms of test-performance from this effect.

So what I meant (expressing it poorly) is that seeming paradoxical effects of stimulants (eg, calming, drowsiness) aren't actually THAT much more common among those with ADD than others.

For people with high IQs and not suffering from ADD/ADHD, the effect of these medications was especially small.

Mmmm...perhaps pedantically, there's a logical problem with sorting our subject groups by IQ but also using IQ tests as our dependent measure. Eg, those with high IQs benefit little from stimulants 'cause they already possess whatever characteristics are useful for scoring high on IQ tests. Speculating, though, such individuals might be more top-down cognitively directed and motivated to begin with.

ebola

 

[IHateOpiophobes]

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.

My doctor takes the stuff himself on occassions and he made it sound like speed except he had never done speed....so I dont think he realized. I noticed the effects the first time. Its just so subtle. Which I think I love about the drug...is there is no harsh side effects. No real ups or downs.

The package says nothing about that.

 

[IHateOpiophobes]

Its like what codeine is to oxycodone.....nuvigil is to dextromethylamphetamine. (NASTY METH)

IMO

 

[Solipsis]

I don't insufflate crushed tablets, it's pure powder. Additionally it causes the least irritation to the nasal mucosa of pretty much any compound that's been up there.

The modafinil is bumped but I don't weigh it because the amount of material that fits on the tip of a little metal lab spatula used to bump is effective and very fast at that. So that is my ´unit´ for a dose amount. One or two repeats may make the effect much more prominent but 1 or 2 are enough to get the eyes wide open. Very much the wakefulness promotion rather than stimulation.
I bet the amount of a bump is 10-25 mg, that is definitely a significant difference with oral doses of 200 mg a tablet!

Mild palpitations and signs that I have taken more than enough was noticed after about 8-10+ bump but it was absolutely not alarming at any point, that points to a good therapeutic index overdose-wise although I am not making any toxicity claims.

 

[Epsilon Alpha]

I don't speak Russian(?) but I love the bump!
If I recall correctly one of the main MOA uncovered currently:
- Alpha1 agonist
- D2 agonist
- DAT inhibitor (closing it in a novel formation)
- Modulates gap junctions via a Ca++ dependent enzyme

 

[laCster]

ok snorting nuvigil is not cool, it gave me the worst nasal irritation of my life, it fucking sucked..


idk i mainly use modafinil as a 3A4 inducer to boost the amount of norbup converted from bup...

but bump on this thread


i also agree that nuvigil (modafinil) goes well with amphetamines. i took roughly 75mgs nuvigil with 15mgs Adderall and it felt like 20-30mgs addyt

 

[Hammilton]

I did not know about the bup to norbup conversion. I'll have to look into that. I take 150mg of Nuvigil daily. It's a wonderdrug, imho. Absolutely zero side effects and lots of positives! No compulsion to take or to take more, either.

 

[amanitadine]

Ham, I trust your take more than most, even when it comes to subjective effects, as it is clear you still keep your discerning mind. So, your phrase "wonder drug" caught my eye (heavy words!). I've never tried nuvigil, just modalert years ago, in all sorts of doses, with basically no effect other than what I assumed was placebo. Is nuvigil that much better, more than just 2x as strong, or is there something negative going on in the "inactive" isomer of modafanil? Or is this individual just not susceptible to these mild effects? Still got my curiosity here. . . .

 

[AlphaMethylPhenyl]

I did not know about the bup to norbup conversion. I'll have to look into that. I take 150mg of Nuvigil daily. It's a wonderdrug, imho. Absolutely zero side effects and lots of positives! No compulsion to take or to take more, either.

What else do you take? The effects your experiencing are probably somewhat contingent on any other drug you regularly ingest.

 

[MeDieViL]

Eg, those with high IQs benefit little from stimulants 'cause they already possess whatever characteristics are useful for scoring high on IQ tests.

Focus, speed of thinking and productivity are not related to IQ but improved by stimulants so i disagree with this statement.

the hallucinations being particularly relevant in disorders like schizophrenia, which, interestingly enough, Provigil is being used to treat.

It improves the conditions negative symptions in combo with a ap wich shire has shown to do succesfully with amphetamine too.

At this point I have to chime in...
Why are you guys snorting modafinil at all? There is no rush of upcoming effects, not even when injecting the drug AFAIK. Bioavailalibity seems to be sufficient. So why the heck putting such stress to your nose mucosa?

Please enlighten me. Thx!


- Murphy

Improving bioavailability is the latest trend here, im not really a trendfollower and just take more of things.

 

[Hammilton]

Focus, speed of thinking and productivity are not related to IQ but improved by stimulants so i disagree with this statement.

Speed of thinking is definitely related to IQ. Much of IQ testing is timed, and the more rapidly you can process your thoughts, the higher your score will be.

I don't know about productivity, but focus and speed of thinking will both be deeply beneficial in taking an IQ test, just like with any test.

 

[laCster]

I did not know about the bup to norbup conversion. I'll have to look into that. I take 150mg of Nuvigil daily. It's a wonderdrug, imho. Absolutely zero side effects and lots of positives! No compulsion to take or to take more, either.

yah, buprenorphine is metabolized into norbuprenorphine (full-agonist to mu receptors) through cytochrome 450 3A4. modafinil is a potent inducer of 3A4, and so when i take the too together, i get a foreign sensation, i feel good, my body feels sleepy and stoned, and my eyes feel heavy and are pinned. the feeling is a little subtle, but i can definitely tell when there is more norbup on my receptors than bup because the effects feel different. usually i take 150mg nuvigil with .5-1mg suboxone in the morning, and after about 4-5 hours, i start to feel more talkative than usual, my anxiety, decreases, and i crave nicotine..

if anyone has similar effects please post!! i mean tagamet definitely does it's job well and i can really tell if i have taken cimitidine to potentiate a benzo or opiate, so shouldnt the opposite of inhibiting 3A4 accurate aswell? if tagamet noticeably increases duration and potency by inhibiting enyzmes including 3A4, then shouldnt modifinil noticeably increase th effects of norbup? i think so, but i don't have any study or grounds to go on/...

please post if you have experiences with using modafinil as a 3A4 inducer


i like modafinil too, it has very little side effects besides the fucking headaches i get sometimes. modafinil does it's job as being a wake-fullness promoter, and helps with focus and motivation to do work. it is very handy when i have not had alot sleep because after i take modafinil, i feel like i had 8hrs of sleep and good to go. however, it does take a while to kick in IMO, so i like amphetamines better. i think amps are all around better, but if i just need to wake up modafinil is awesome. nuvigil's best ability is to wake you up IME and this can be very handy when studying for finals, working late, driving long distances, the list goes on and on. also modafinil doesnt have much euphoria which is a plus for actually studying because on amphetamines i get euphoric and sometimes i am distracted by this...