How does modafinil work ?

[Dr. Beat]

I have been taking adrafinil and modafinil a few times a week for the last year, and it is a good 'back ground' drug, especailly useful for work.

In the sales pitch on the companies that sell it, they say it is a alpha1-adrenic receptor agonist, but i have read else where that is does not hit that receptor.

One article said it inhibits the GABA neurons that normally slow down the histamine neurons, so basically it causes extra histamine activity.

Does anyone have any presice info on how this drug work?

 

[BilZ0r]

Answer that question and you'll get a publication in a fancy journal. It's something to do with histamine, orexin and noradrenaline, but which is cause and which is effect is unknow. It doesn't increase noradrenaline release (at least it doesn't need to, to promote wakefulness), but it does need to bind to noradrenaline receptors. It does increase histamine release... (which should decrease noradrenaline release, believe it or not).

But I don't know, (can you link me to the article that said "it inhibits the GABA neurons that normally slow down the histamine neurons").

 

[Jamshyd]

I don't know about Histamine but a simple search on pubmed yeilds several studies that shows that Modafinil plays around with GABA and Glutamate levels (Increases the availability of the latter and decreases the former, I believe.). Of course, as bilzor suggested, the exact mode of action remains unclear.

Sounds like a nightmare for someone like me who is semi-dependent on benzos and Ketamine for mood stability . lol.

 

[VelocideX]

I'm with bilz0r. I've read most of the abstracts on pubmed, and a lot of them hint at central histamine release, noradrenaline reuptake inhibition on wake-promoting neurons or modifications to the oxrein system.

Having tried it, I can say that it's truly fantastic. It doesn't make you hyper, or awake... you just don't feel tired.

Having said that after an hour or two I feel very focussed, for a period of perhaps 2 hours. I find it very easy to imprint memories in this time

 

[nanobrain]

just got the latest Sigma Cell Signalling and Transmission Catalog, there is an article on sleep-wake biopharmacokinetics of a few agents, moadfinil included.

the answer - they dont fuckin' now! effects DA release and reauptake, 5HT, NE, + histamines, and others, but the mech remains unknown as of 21 September 2005.

 

[eternalcrux]

just for the record... i had a brief trial with modafinal... i managed to get my psych to prescribe it for my 'add' because among other reasons i worry about (my ever-growing) amphetamine tolerance/addiction... so...

I have tried upto 400mgs by itself and experienced feelingsof anger, dysphoria, but at least i was akake ;\
it helped with the amp addiction, but in the end i'd much rather stay on amphetamines

was moderately pleasant the first time i used it... more socialble, a tiny amount of euphoria, decreased appetite...

i have combined it with both amps and ritilin... i would suggest tryingit with low doses of amphetamine....

 

[Jamshyd]

I have tried upto 400mgs by itself and experienced feelingsof anger, dysphoria, but at least i was akake ;\

Irritability? Dysphoria? Sounds like you neeeeed..... less glutamate and more GABA? :D

 

[Dr. Beat]

i find modafinil REALLY good once a week, or pretty good twice a week, and i can really feel it then. But taking it every day it is too back ground, and too expensive.

BilZor - you asked for that paper:

http://www.jneurosci.org/cgi/content/abstract/20/22/8620

and this:

http://www.anakata.hack.se/index/referenser/modafinil/biol.psychiatry.55.1031-1040.2004.pdf

the last page has the bit about modafinil reducing certain GABA neurons that normally inhibit histamine neurons.

 

[BilZ0r]

I see, so there's no real evidence of it, they're just geussing.

 

[yaesutom]

Well! I'm not so sure i like this modafinil stuff.... hmm..

Given its
marked lack of effect on catecholamine receptors, recent findings
that modafinil substantially increases histamine release in
the anterior hypothalamus of the rat (Ishizuka et al 2003) were of
particular interest. The authors propose that modafinil’s action in
the ventrolateral preoptic area (VLPO) of the hypothalamus
(Scammell et al 2000) acts to disinhibit the gamma-aminobutyric
acid (GABA)ergic input from the VLPO to the tuberomamillary
nucleus (where cell bodies of the histaminergic system are
located) (Sherin et al 1998). This, in turn, promotes histamine
release and the resultant wake-promoting action of modafinil.

Man, so I took ~400mg yesterday, all was well actually, then ~300mg today, but dayum, little TOO stimulated (more stimulated than when I tried it before, "rumor/discussion" about this particular modafinil i have might be only one isomer).

So i've taken Plenty of a benzo to counteract this but it seems as if King Moda. is overriding little benzo. Huh. Well I guess thats the first time i've ever had a situation where a benzo *didn't work*. Its literally like blocking its action totally... wierd.

So, I suppose i'm stuck all hyped up like this for a while... some of yesterdays dose definitely added to today's dose.

 

[Smyth]

But what do u think of modafinil? Personally I dont think I will ever try it. I guess that peoples choice in drugs is somewhat personalized and I just dont see myself wanting to go near something like that. But the fact that it is even available means one of two things. Either it is somewhat experimental still or it is a tried & trusted medicament.

 

[paradoxcycle]

Modafinil is a dopamine reuptake inhibitor. This much is actually admitted in the Provigil labeling, which says:

"In vitro, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release mechanism ... In addition to its wakefulness-promoting effects and increased
locomotor activity in animals, in humans, Provigil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as stimulant-like."

That's heavy stuff for a compound that's been relegated to Schedule IV. That information, taken from the "Mechanism of Action and Pharmacology" subsection of the "Clinical Pharmacology" monograph in the official labeling, really tells you everything you need to know about modafinil. It's a DRI. It's a highly effective antidepressant, relative to the SSRIs and other mixed-action inhibitors of 5-HT and norepinepherine reuptake, and "atypical" compounds like mirtazapine and bupropion. Any "antidepressant" that's really effective, virtually by definition, is going to elevate mood. Modafinil does that. It's especially effective when used to "augment" the action of traditional antidepressants. It has no official indication for such use, but psychiatrists are slowly beginning to discover how well it works.

When I look at the modafinil molecule, and try to visualize it unraveled in solution in its three-dimensional form, I see something with much more resemblance to cocaine than to methylphenidate (or amphetamine). The two bulky rings (although in cocaine one of them is aliphatic) and the two ketones (although in modafinil one of them is actually a thionyl rather than a carbonyl group) are the key features.

 

[BilZ0r]

Yeah, I doubt it eh. There certainly is some evidence that it could be, like that
Mice with no DAT don't get the modafinil wake up call and that Modafinil protects against MPTP toxicity.

HOWEVER:

Modafinil causes an incredibley marginal increase in extracellular dopamine at wakepromoting doses[1, 2]. Though not everyone agrees [3] (These people think it's action potential dependent [4].

It seems to have DAT affinity around 1-3uM[5]. Indeed, there seems to be some strange interaction with cocaine, that might be explained by low DAT occupancy [6].

But then seeing as modafinil gets to around 10uM in the plasma in clinical trials [7], that might be possible to block DAT quite well...

So I just don't know.

 

[yaesutom]

The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30-300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (beta-p-chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 microM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 microM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 microM), whereas it was increased by the GABAB receptor agonist (-)-baclofen [beta-(p-chlorophenyl-gamma-aminobutyric acid)] (10 microM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.

Interesting. Well it got me nice and wired first day at 400mg, next day took more and felt "too" wired, ate some benzo's, didn't do anything, so i'll agree it "seems to reduce GABA transmission" and shizzle. But it actually seemed to pretty much block the benzo's effects, unlike amphetamine or methylphenidate where I can feel both drugs - stimulated and focused, but relaxed at the same time.

Hmm... well I wonder about other routes of administration?

 

[raybeez]

Interesting. Well it got me nice and wired first day at 400mg, next day took more and felt "too" wired, ate some benzo's, didn't do anything, so i'll agree it "seems to reduce GABA transmission" and shizzle. But it actually seemed to pretty much block the benzo's effects, unlike amphetamine or methylphenidate where I can feel both drugs - stimulated and focused, but relaxed at the same time.

Hmm... well I wonder about other routes of administration?

Aren't benzodiazepines are metabolised by CYP3A4? Modafinil is a potent inducer of CYP3A4/5 activity. I have a modafinil rx and I've definately noticed it cut the duration of some other drugs metabolised by CYP3A4 by up to 75%.

 

[Smyth]

Modafanil is an interesting compound; it is structurally unrelated to any known antidepressant. It has been used in France for a number of indications including depression, although there have as yet been no published studies establishing clinical antidepressant efficacy. Most of the published investigations have examined its psychostimulant properties in humans and animals (10). It has been tentatively classified as an a1-adrenergic agonist based on the ability of a1 antagonists to block its behavioral activity in animals. Another French compound, adrafinil, is also classified as a central a1 agonist and is said to be helpful for depression and other symptomatology in cognitively impaired subjects (22).

http://www.acnp.org/G4/GN401000109/CH107.html

 

[specialspack]

Aren't benzodiazepines are metabolised by CYP3A4? Modafinil is a potent inducer of CYP3A4/5 activity. I have a modafinil rx and I've definately noticed it cut the duration of some other drugs metabolised by CYP3A4 by up to 75%.

Interesting.. any more info on this?

 

[jasoncrest]

Aren't benzodiazepines are metabolised by CYP3A4? Modafinil is a potent inducer of CYP3A4/5 activity. I have a modafinil rx and I've definately noticed it cut the duration of some other drugs metabolised by CYP3A4 by up to 75%.

Interesting.. any more info on this?

http://medicine.iupui.edu/flockhart/table.htm

Scroll down to the Inducers list, you will see that Modafinil induces CYP3A4,5,6.
So it will make the body eliminate some benzos and opiates much faster than usual...
(Valium, Xanax, Morphine, Methadone etc... for exemple will last much shorter)

 

[Solipsis]

If part of modafinils mechanism of action employs gabaergic inhibition, can modafinil be used when someone took a little bit too much GHB / GBL ?

 

[konshuss]

This is a very interesting thread, too bad it seems to be in hibernation.

I've been occasionally experimenting with moderate doses of Adrafinil and finding it to be living up to its reputation. It's a very strange animal!

Feeling "awake", but not "hyper". Normal mental faculties. It's like you feel "extra-normal". But sleep is out of the question. Sometimes this is desirable.