26 replies to this topic

[ikaros]

Both are dopamine reuptake inhibitors, both also moderately affect norepinephrine. Take for example Wikipedia's description of the pharmocodynamics of these drugs:


For modafinil:

The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine. While co-administration of a dopamine antagonist decreases the stimulant effect of amphetamine, it does not negate the wakefulness-promoting actions of modafinil. Modafinil activates glutaminergic circuits while inhibiting GABA. 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.

For cocaine:

One significiant effect of cocaine on the central nervous system is the blockage of the dopamine transporter protein (DAT), hence cocaine is called a dopamine reuptake inhibitor. Brain regions that are rich with dopaminergic neurons are the ventral tegmental area (VTA), the nucleus accumbens and the prefrontal cortex.

A monoamine transmitter that is released by a neuron for signal firing is normally recycled via the transporter to terminate the signal and to spare transmitter resources. The transporter binds the transmitter and pumps it out of the synaptic cleft back into the pre-synaptic neuron. There it is taken up into storage vesicles. Cocaine binds tightly at the DAT forming a complex that blocks the transporter's function, this also blocks the reuptake of the transmitter. Once released into the extracellular space (synaptic cleft) dopamine accumulates there, because the recycling mechanism is inhibited by the cocaine. This results in an enhanced and prolonged firing (boosted signal transduction).

Cocaine is also a less potent blocker of the norepinephrine transporter (NET) and serotonin transporter (SERT).

So the bottom line is that the cognitive enhancing effects come from the increased dopamine and norepinephrine (though modafinil does have other routes also and doesn't seem to have the euphoric effect). The only difference I can currently come up with is that modafinil is just many times milder cocaine but in principle the same infamous drug everyone claims to be as one of the main killers of brain cells. So anyone with more prfound insight into psychodrugs could explain why I shouldn't be afraid to take modafinil. PS. I could have also replaced cocaine with amphetamine as their mechanisms are similiar.

[emerson]

Explain the difference between a tsunami and a slightly chilled bottle of water sitting in someone's fridge. I'm not familiar enough with the research on cocaine and modafinil to really state much about how either work. But I did want to at least offer one nit-pick in your method of analysis. The first, and I don't mean this as an insult, is that your descriptions of both their methods of actions are very crude. It can come from necessity of the means of best communication, but the end effect boils down to describing danger in terms of vague blurs of colour rather than a gun held in someones hand. The blur might be a gun, and the environment can be suggestive of that. But a blur might also be an apple or a cell phone. In much the same way, a drugs description of modification of dopamine levels as a mechanism of action could be significant correlation or just a red herring when it comes to determining end effect on a body.

As to why you should be afraid of modafinil, I'd say for the same reason one should be scared of any psychoactive substance which hasn't had extensive long term studies. It's the same reason that broad overviews of a substances proposed mechanisms of action can't be used as assumptions for how it will affect things overall. Mainly it's just that at this point, we gain the data avalanche from experimentation. And where there's gaps in the experiments filled with guesswork, no matter how educated the guess, history's given pretty good evidence that the actual reality will be different than expected.

[doug123]

Explain the difference between a tsunami and a slightly chilled bottle of water sitting in someone's fridge.

No kidding.

Emerson: were you aware that modafinil is used to help those addicted to cocaine? It seems to blunt the effects.

http://www.annalsnya...ract/1003/1/328

GLUTAMATE AND DISORDERS OF COGNITION AND MOTIVATION

Volume 1003 published December 2003
Ann. N.Y. Acad. Sci. 1003: 328–345 (2003). doi: 10.1196/annals.1300.021
Copyright © 2003 by the New York Academy of Sciences

Glutamatergic Agents for Cocaine Dependence


CHARLES DACKIS AND CHARLES O'BRIEN

Treatment Research Center, University of Pennsylvania, 3900 Chestnut Street, Philadelphia, Pennsylvania 19104, USA

Address for correspondence: Charles Dackis, Treatment Research Center, University of Pennsylvania, 3900 Chestnut Street, Philadelphia, PA 19104. Voice: 215-662-8752; fax: 215-243-4665.
Dackis@mail.med.upenn.edu
Ann. N.Y. Acad. Sci. 1003: 328-345 (2003).


Effective medications for cocaine dependence are needed to improve outcome in this chronic, relapsing disorder. Medications affecting glutamate function are reasonable candidates for investigation, given the involvement of glutamate circuits in reward-related brain regions and evdence of cocaine-induced glutamatergic dysregulation. In addition, it is increasingly apparent that glutamatergic mechanisms underlie several clinical aspects of cocaine dependence, including euphoria, withdrawal, craving, and hedonic dysfunction. Even denial, traditionally viewed as purely psychological, may result, in part, from dysfunctional glutamate-rich cortical regions. We review the involvement of glutamate in reward-related circuits, the acute and chronic effects of cocaine on these pathways, and glutamatergic mechanisms that contribute to the neurobiology of cocaine dependence. We also present preliminary data from our research of modafinil, a glutamate-enhancing agent with promise in the treatment of cocaine-addicted individuals.

Key Words: cocaine • glutamate • modafinil • pharmacotherapy • craving

Full paper available here:

http://www.nature.co...l/1300600a.html

Neuropsychopharmacology (2005) 30, 205–211, advance online publication, 3 November 2004; doi:10.1038/sj.npp.1300600

Clinical Research
A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence
Charles A Dackis1, Kyle M Kampman1, Kevin G Lynch1, Helen M Pettinati1 and Charles P O'Brien1,2

1University of Pennsylvania School of Medicine, Philadelphia, USA
2Department of Veterans Affairs Medical Center, Philadelphia, USA
Correspondence: CA Dackis, University of Pennsylvania Treatment Research Center, 3900 Chestnut Street, Philadelphia, PA 19104, USA. Tel: +1 215 662 8752; Fax: +1 215 243 4665; E-mail: dackis@mail.med.upenn.edu

Received 8 June 2004; Revised 23 September 2004; Accepted 24 September 2004; Published online 3 November 2004.

Abstract

Despite years of active research, there are still no approved medications for the treatment of cocaine dependence. Modafinil is a glutamate-enhancing agent that blunts cocaine euphoria under controlled conditions, and the current study assessed whether modafinil would improve clinical outcome in cocaine-dependent patients receiving standardized psychosocial treatment. This was a randomized, double-blind, placebo-controlled trial conducted at a university outpatient center (from 2002 to 2003) on a consecutive sample of 62 (predominantly African American) cocaine-dependent patients (aged 25–63) free of significant medical and psychiatric conditions. After screening, eligible patients were randomized to a single morning dose of modafinil (400 mg), or matching placebo tablets, for 8 weeks while receiving manual-guided, twice-weekly cognitive behavioral therapy. The primary efficacy measure was cocaine abstinence based on urine benzoylecgonine levels. Secondary measures were craving, cocaine withdrawal, retention, and adverse events. Modafinil-treated patients provided significantly more BE-negative urine samples (p=0.03) over the 8-week trial when compared to placebos, and were more likely to achieve a protracted period (3 weeks) of cocaine abstinence (p=0.05). There were no serious adverse events, and none of the patients failed to complete the study as a result of adverse events. This study provides preliminary evidence, which should be confirmed by a larger study, that modafinil improves clinical outcome when combined with psychosocial treatment for cocaine dependence.

Keywords: modafinil, cocaine, glutamate, pharmacotherapy, abstinence, addiction

[graatch]

Stir ye the pot? :( Different binding sites. Subjectively, modafinil is not blindingly euphoric. It does not clench my veins. I stayed up through AP Economics.

[ikaros]

Explain the difference between a tsunami and a slightly chilled bottle of water sitting in someone's fridge.

Isn't this a bit far-fetched analogue because both substances bring about significant cognitive boost. I wasn't actually very concerned about the possibility that modafinil would be addictive as it apparently isn't, but the lack of long-term research into modafinil's effect on brain functioning makes me wary. It just might be that modafinil is the new wonderdrug without the damaging effects of other stimulants, however pushing the brain quickly outside its normal functioning as stimulants do compared to for example the slower routes like improving brain's bloodflow through complex mental activity/exercises and supplements, should be still considered as a risky attempt. Though I'm still going to try modafinil to see how it feels and then make up my mind whether it's appropriate for me, it should at least beat methylphenidate which has a bad effect on me and doesn't improve my slight concentration difficulties.

[nootropicinfo]

Methylphenidate and cocaine cause increased dopamine (which is what makes them addictive). Not only is dopamine release with modafinil not dose dependant, it doesn't inhibit the re-uptake either like other amphetamines.

[ikaros]

Methylphenidate and cocaine cause increased dopamine (which is what makes them addictive). Not only is dopamine release with modafinil not dose dependant, it doesn't inhibit the re-uptake either like other amphetamines.

No, modafinil does have its dirty hand in dopaminergic systems, and with great probability interferes with dopamine reuptake.

Dopaminergic role in stimulant-induced wakefulness.Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM.
Sleep Disorders Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305, USA. jwisor@stanford.edu

The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil.

PMID: 11222668 [PubMed - indexed for MEDLINE]

Although reading other studies clearly points out that modafinil compared to amphetamines is much more selective in choosing the brain regions where it does its magic: crudely put, amphetamines flip all the switches, whereas modafinil only few.
Btw monkeys make no discrimination between cocaine and modafinil: both "taste" as good.

[brutale]

Modafinil and cocaine may both affect dopamine reuptake, but they are different drugs. Endorphins (from exercise) and morphine both bind to opioid receptors, but we recognize that they are different substances with different effects (and some similar effects too). Likewise with coke and modafinil.

One of the biggest differences is that cocaine (in most people) induces intense euphoria, which quickly turns into a nervous/anxious/wired state. The user then needs to take more cocaine to try to recover the euphoric state, or use some sedative (e.g. alcohol or a benzo) to "come down." If you've done this or have observed this, you know what a sh*t-show it is. By contrast, Provigil does not produce intense euphoria (some people get mild euphoria) and does not cause an anxious "coming down."

Cocaine produces extreme vasoconstriction. Users report "milky vision," and typically have elevated pulses as their hearts pump harder against constricted vasculature. The vasoconstriction leads to massive release of free radicals, apparently, and potential tissue damage. My impression is that many of the destructive effects of cocaines stem from ischaemia. By contrast, Provigil does not normally cause notable vasoconstriction. My pulse rate is basically unchanged whether I use Provigil or not.

Cocaine is quite addictive. The mechanism is not that well understood. Some of the addictive properties are evidently based on deep-seated memories of euphoria. Some work suggests that depleted glutamate levels play a key role in coke addiction. NAC and modafinil are both effective at raising glutamate levels, and both are effective treatments. I don't know if any clinician has attempted to use MSG to treat cocaine patients!

My ex-girlfriend had (or has, I don't know if she is sober) cocaine problems which she managed to conceal from me until we got very close. I tried to help her with her issues, but finally gave up on the situation. FWIW, she seemed to like NAC (about 4g/ day) which cut her usage in half. She didn't like Provigil. I think the issue was that Provigil interfered with her "high." No fun for her. But her problems were no fun for anyone else - hence my giving up on her eventually. Cocaine is bad news.

If you have some first-hand or second-hand experience with cocaine usage, there is no confusing cocaine and provigil. So, although cocaine and provigil both influence some of the same neurotransmitters, it is easy to see how different the effects are. If provigil were simply mild cocaine, or something very like that, the effects would be similar to those of doing, say, 1/2 line of coke. But the effects are manifestly different.

My two cents.

Edited by brutale, 30 September 2006 - 02:23 PM.

[systemicanomaly]

How about the Vasopressin (ADH) connection?

'Tis my understanding that stimulants such as Cocaine, XTC, Ritalin & other amphetamines cause the pituitary to release Vasopressin. This vasopressin release is responsible for some of the pleasurable effects of cocaine. Vaso is also a major factor in the positive cognitive effects of many of these stimulants (incl cocaine). However, frequent use of these drugs can lead to sluggish mental performance and depression resulting from vasopressin depletion.

Is NE1 aware of a connection between Modafinil & vasopressin? Does it trigger a release? Does chronic use of Modafinil lead to vaso depletion?

[nootropicinfo]

QUOTE
Methylphenidate and cocaine cause increased dopamine (which is what makes them addictive). Not only is dopamine release with modafinil not dose dependant, it doesn't inhibit the re-uptake either like other amphetamines.


No, modafinil does have its dirty hand in dopaminergic systems, and with great probability interferes with dopamine reuptake.

QUOTE
Dopaminergic role in stimulant-induced wakefulness.Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM.
Sleep Disorders Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305, USA. jwisor@stanford.edu

The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil

PMID: 11222668 [PubMed - indexed for MEDLINE]



Although reading other studies clearly points out that modafinil compared to amphetamines is much more selective in choosing the brain regions where it does its magic: crudely put, amphetamines flip all the switches, whereas modafinil only few.
Btw monkeys make no discrimination between cocaine and modafinil: both "taste" as good.


I'm sure this is right - perhaps I should re-phrase it to:

Methylphenidate and cocaine cause a huge increase in dopamine (which is what makes them addictive). Dopamine release with modafinil doesn't seem to be dose dependant, and i'm sure it doesn't inhibit the re-uptake to the extent of these amphetamines also.

Refering to the previous quote:

Explain the difference between a tsunami and a slightly chilled bottle of water sitting in someone's fridge.

You have found two descriptions which explain similar actions. The extent to which these processes occur differs quite considerably. It cannot be summed up in a couple of paragraphs (hypicrital given my post, i know).

Fact is, if you were to compare large doses of ritalin/cocaine with modafinil personally you wouldn't be asking this question.

[nootropicinfo]

Btw monkeys make no discrimination between cocaine and modafinil: both "taste" as good.


I don't believe this for a second. Cocaine tastes much better! Also the feeling is much more euphoric. A crash is then experienced which can be postponed by boosters. Modafinil has a milder effect. Just can't be true.

[blarger]

Subjectively, they always felt the same, except that cocaine gets there faster. I'm not convinced that modafinil is a good long term solution if you really care about your health... no free lunches.

[ikaros]

I don't believe this for a second. Cocaine tastes much better! Also the feeling is much more euphoric. A crash is then experienced which can be postponed by boosters. Modafinil has a milder effect. Just can't be true.

No offence, but are you an ape? If not, how would you know what a nonhuman primate thinks of these drugs. [lol]

[emerson]

Anyone listen to Coast To Coast AM? As embarrassed as I ever am to admit that I do, there was a great interview on a couple days back with the writer of 'Radical Evolution'. He mentioned modafinil, and surprisingly that he was using it. What followed was one of my main joys for listening. An absolutely manic woman in, ranting about how people using this "new kinda meth" would be rampaging across the nation to the beat of their satanic master. OK, I'm exaggerating by a small margin. But the gist of it came down to a steep curve these kinds of technologies are going to have to overcome in the popular mind.

[nootropicinfo]

No offence, but are you an ape? If not, how would you know what a nonhuman primate thinks of these drugs.  [lol]

My pet monkey and me enjoy the odd coke binge from time to time.

[ikaros]

My pet monkey and me enjoy the odd coke binge from time to time.

[thumb] Well the main thing's that you're both happy, nothing beats that. [lol]

[kottke]

lol. I wish i had a pet monkey when i abused cocaine. We'd be up all night monkeying around. I mean imagine showing up to a party or a freind's place with your pet monkey and asking him to try the first line of coke and then him signaling you with a- [thumb]

Just stating that i have used cocaine myself i will tell you that the effects of modafinil are pretty close. There's really no comedown which is good, but the racing thoughts of grandeur and world philosophys are increasingly aparent. These symptoms may not be present in non previous cocaine users and they do seem to go away with continued use. A few weeks back I gave my freind, a teacher, who also used to abuse cocaine (funny that he's teaching kids now) and we had been at the bars till about 3 or so. He had to work the next day so i stopped by my house and grabbed him a 200mgs tab of modafy.

He felt really good off of it and he made statements like "dude i felt like i was on f*cking cocaine all day but better.I was looking at the classroom and knew how many students were there immeditely. Id be talking to a few students at a time and would notice if any of there shoe lasses were untied while still in conversation"-"your going to have to give me some more of that stuff sometime so i can sit down and right a novel or something".

It's too bad it causes major anxiety in prone individuals. I really liked it because of the increased production level. Just gives me insomnia, cocaine dreams, and horrible anxiety. It most certainly is in the realm of cocaine nastalgia. If you have used cocaine you will know what im talking about.


PS-Never do cocaine, ever. [mellow]

[ajnast4r]

Explain the difference between a tsunami and a slightly chilled bottle of water sitting in someone's fridged.

HAHAHA

[mitkat]

lol. I wish i had a pet monkey when i abused cocaine. We'd be up all night monkeying around. I mean imagine showing up to a party or a freind's place with your pet monkey and asking him to try the first line of coke and  then him signaling you with a- [thumb]

It's funny, because I can picture the whole scenerio so clearly. More importantly, would he be wearing a fez hat and red velvet vest? That monkey would make every party a four alarmer.

[cmorera]

from what I was talking with Adam earlier, Modafinil doesn't cause dopamine increase / or flooding in the brain, whereas cocaine or drugs of abuse will obviously be linked with major neurotransmitter activity ... so this is one reason why I am more confident in taking it, the last thing i needs is to be addicted to something.

[coolio]

Cocaine and methylphenidate aren't amphetamines, first off. Amphetamines don't even inhibit dopamine reuptake to any significant degree, they just cause massive efflux of dopamine (like MDMA does with serotonin).

Cocaine is much different from modafinil in almost every way, even in regards to the areas of the brain where it inhibits dopamine reuptake. Cocaine will raise dopamine levels in the prefrontal cortex to the levels required for intense euphoria within seconds if injected - modafinil doesn't have any known dopamine reuptake effect in the prefrontal cortex. Cocaine also has effects on serotonin release, which is crucial for the perception of euphoria. Neither dopamine nor serotonin release alone cause euphoric effects, but when combined, different ratios result in different perceived levels of euphoria.

[cmorera]

Cocaine and methylphenidate aren't amphetamines, first off. Amphetamines don't even inhibit dopamine reuptake to any significant degree, they just cause massive efflux of dopamine (like MDMA does with serotonin).

Cocaine is much different from modafinil in almost every way, even in regards to the areas of the brain where it inhibits dopamine reuptake. Cocaine will raise dopamine levels in the prefrontal cortex to the levels required for intense euphoria within seconds if injected - modafinil doesn't have any known dopamine reuptake effect in the prefrontal cortex. Cocaine also has effects on serotonin release, which is crucial for the perception of euphoria. Neither dopamine nor serotonin release alone cause euphoric effects, but when combined, different ratios result in different perceived levels of euphoria.

point, Modafinil

I am the kind of person who tends to OVERSLEEP, like over 9 hours ... but I konw many people are sleep derpirved in the world, who get less than 7 hours .. so in these cases I dont think Modafinil would be a good suggestion simply since there is probably a minimum amount of sleep needed for certain regulatory brain functions, ext...

[morb]

People who like modafinil are going to defend it, even to the point that faileth human understanding. A new drug that does something pretty intense in my mind also sets off warning bells. There is always a price to be paid, if you can convince yourself it's nothing more than the so-called "decreased language ability", then enjoy. Ever actively try concentrating? Afa amphetamines, they are like steroids in pro-sports to med-students, and the doctors they become aren't dumb. One of the most thoroughly tested and studied drugs of all time. Maybe you have too much dopamine already if you can't concentrate and that's why most people who therapeutically use amphetamines for cognition eventually can do it on their own. I'm not saying undue apoptosis actually does occur, that is a debate. But as with modafinil, when you upset homeostasis the body will adjust.

[morb]

...absolutely...retarded...ignorant...unsubstantiated...me

Project much? Btw are you in harvard med? Didn't think so...

[nootropicinfo]

Cocaine and methylphenidate aren't amphetamines, first off. Amphetamines don't even inhibit dopamine reuptake to any significant degree, they just cause massive efflux of dopamine (like MDMA does with serotonin).

Cocaine is much different from modafinil in almost every way, even in regards to the areas of the brain where it inhibits dopamine reuptake. Cocaine will raise dopamine levels in the prefrontal cortex to the levels required for intense euphoria within seconds if injected - modafinil doesn't have any known dopamine reuptake effect in the prefrontal cortex. Cocaine also has effects on serotonin release, which is crucial for the perception of euphoria. Neither dopamine nor serotonin release alone cause euphoric effects, but when combined, different ratios result in different perceived levels of euphoria.

This is the the most accuarate post from what I have researched. Thanks for that.

[variance]

.... if he bothered to pick up a cellular and molecular biology book this thread would not be necssary... it's no simple as saying this neurotransmitter is responsible for this in this drug.. hey.. these two drugs work on the same neurotransmitters

They must do the same thing and have the same EVIL properties

OMG

EVILLLLLLL

DESTROYS SOCIETY

Give me a break. why don't you put down the pubmed and medical journals
and learn some basic biochem/cellmolec or pick up a neuropharmacology book if you have prior g-bio and g-chem/o-chem experience.

It doesn't take a med-school student to understand this shit.
any educated (as in learned/understood/gained perspective.. not memorized)
bio undergrad or grad student can figure this out.

oh... yeah.. i'm being facetious..
not sure if you'd be able to tell judging by your question.

in laymen terms:
basically your question is a stupid one and you're obviously too lazy to do the leg-work to spend a few hours getting perspective.

[ikaros]

in laymen terms:
basically your question is a stupid one and you're obviously too lazy to do the leg-work to spend a few hours getting perspective.

Thanks for the "constructive" criticism, but the question was posted a long time ago in a reasonable scepticism, so you're point arrived like an old newspaper without a value.

OMG

EVILLLLLLL

DESTROYS SOCIETY

My stance is rather positive towards modafinil than it's negative. My personal conclusion was rather that modafinil should be used with caution (e.g. I've gone through some of modafinil's bizarre effects on behaviour), but that doesn't implicate that it will bring down society [wis] .

Btw would you then care to give that golden perfect reference to one study that exhaustively explains modafinil's action in the brain and the associated effects. Doing so you could avoid many of these annoying questions in the future.