That Wacky Modafinil

[Silverfox]

Mandark, I'd agree with edarrin. There have been times when I have taken 100mg modafinil (that's the dose that works for me) every other weekday for weeks on end, then when circumstances have changed none at all for weeks without even noticing.

When using it I find I only need it every second day because the day after taking it I feel unusually refreshed and clear headed.

 

[irobeth]

Mandark, I'd agree with edarrin. There have been times when I have taken 100mg modafinil (that's the dose that works for me) every other weekday for weeks on end, then when circumstances have changed none at all for weeks without even noticing.

When using it I find I only need it every second day because the day after taking it I feel unusually refreshed and clear headed.

This is true _except_ if you take it long enough you will grow to expect that your capacity for work is always the same as if you are taking modafinil. I mean this to say if you aren't taking modafinil you will find that you are more 'weak' or disadvantaged in stamina.

As long as you aren't consistently overstepping your normal bounds while using modafinil you will be okay; just don't use it to reach places you otherwise couldn't.

Case in point: I am still hurting (broken, even) from friday's 5-hour sprinting fest.



About dose size:

However, it appears to be higher than oral LD50 of caffeine. Basti and Jouvet ( 1988 ) describe a suicide attempt using 4500 mg of modafinil; the suicidee survived with no long-term effects but temporary nervousness, nausea, and insomnia

Modainil does release dopamine and norepinephrine, so it might make sense that wellbutrin would interact strongly with it.

 

[ASLEEP4DAYS]

i recall the suicide atempt it was a girl in cali she suffered tachaycardia {increased heart rate} where the immediate effects , you would have to expect that taking that much stimulant , im surprised her heart didnt explode

 

[dokomo]

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.

I have had two different indian brands (One was ModAlert and one was ModPro I think) and name-brand Provigil and I can assure you that name brand Provigil is far different from the Indian generics. I don't know if there is some enantiomeric contamination issues or something, but Provigil was hands-down the best one.

 

[negrogesic]

I had a strange experience mixing provigil will adderall; my vision was tinged orange, had a mild-anxiety attack, and felt overall quite dysphoric.

I would imagine that if there no actual withdrawal syndrome, there must be some sort of rebound fatigue upon abrupt discontinuation after long periods of usage at dose.

Had a girlfriend recently (20 years old) who had been taking 250mg of seroquel/day for "bi-polar" disorder (despite never having any symptoms of the disorder other than "depression" as a 15 year old). Furthermore, she was also on varying amounts of tranxene, which she combated with 200mg/day of provigil. But, she was literally the best looking jewish girl i have ever seen (father was the jew, mother a blond). Still the neurosis from her father carried down to her and proved to much for me. Im actually 1/4 jewish but I can't stand the cultural, fear, neurosis etc. But like is said, literally the hottest jewish girl i've yet to see (tall order, I know). Kauft nicht bei juden.

Figured this was relevant....

 

[Silverfox]

I have had two different indian brands (One was ModAlert and one was ModPro I think) and name-brand Provigil and I can assure you that name brand Provigil is far different from the Indian generics. I don't know if there is some enantiomeric contamination issues or something, but Provigil was hands-down the best one.

That is interesting, and something that I have heard reported elsewhere. I have only tried the branded Modalert from Sun Pharma, which I have purchased over the web but mostly directly from local pharmacies in India (for 1/10 the price!) and I have not experienced any quality issues with the generic product. However, I have found that tablets from the same batch can have quite pronounced differences in effect between doses. I do not attribute this to differences in composition but rather to differences in how the modafinil is working on me at that particular time. For example, one day 100mg might make me quite jittery and on another day really focussed and alert whilst some days I have to up the dose to 200mg ro have any effect. Has anyone else noticed such variation in effect?

 

[Silverfox]

This is true _except_ if you take it long enough you will grow to expect that your capacity for work is always the same as if you are taking modafinil. I mean this to say if you aren't taking modafinil you will find that you are more 'weak' or disadvantaged in stamina.

As long as you aren't consistently overstepping your normal bounds while using modafinil you will be okay; just don't use it to reach places you otherwise couldn't.

Case in point: I am still hurting (broken, even) from friday's 5-hour sprinting fest.

I understand what you are saying but I've tended to use it when living in Goa, where a combination of the heat, the susegade attitude to life and the numerous other distractions can make getting any work done quite difficult. Under those conditions I've found it makes a real difference to my productivity and general motivation. When I get back to the UK things work at such a different pace it is usually a month after my return that I notice I haven't reached for the packet.

 

[drug_FUCKED]

I have had two different indian brands (One was ModAlert and one was ModPro I think) and name-brand Provigil and I can assure you that name brand Provigil is far different from the Indian generics. I don't know if there is some enantiomeric contamination issues or something, but Provigil was hands-down the best one.

I 2nd that, i have purchased modafinil from various sources finding some brands upset my stomach and others cut with caffeine. Provigil is defiantly different to indian brands. I wouldn't use indian pharms too often as they have heavy metal contaminants and strengths often vary.

 

[P A]

modafinil has demonstrated to be quite abuse-proof

Alone, maybe, but in combination with other stims (mostly cocaine, phenidate, and the like), many I know would beg to differ.

Any update on mechanistic stuff? I remember there was a negative study with orexin-knockouts. How about the whole "mobilization of intracellular peptides--->exocytosis of the gap junction" thing? That would probably better explain the indirect reuptake inhibition and the unique stim-potentiating properties...

 

[Phener]

Summary of experience with modafinil:

Psychotic reaction(!)

Went through a period of MASSIVE different types BENZO use, whilst taking MODAFINIL in the morning (reasonable high doses but not massive, i.e 600mg) all while having my nicotine patch (definately synergistic effect with modafinil or at least felt I missed/needed nicotine MORE when on modafinil, so much so I was using the high strength lozenges + patch). RESULT: After a month had what would best be described as a psychotic episode (proper paranoia, crazy thoughts, delusional thoughts etc) Coincided with a time when I could STOP take a few months off and recover. Horrible period in my life.

Ever since then seem to have had a reverse tolerance to the compound (take it very occasionally) I.e take 50mg and thats enough to get me UP in the clouds + stimulated, ODD very ODD, I know appreciate it FAR more and use it very cautiosly when needed on the ODD occasion.

(am totally fine now btw, no psycotic tendancys, never had them, all good)

Now thoughts as to the reason:
1) could have been the benzo's sending me bonkers with the modafinil simply allowing me to tolerate such MEGA doses +/- the NUMEROUS different types, Ironically after my morning modafinil was UP and away no sleepyness but then couldn't get toff to sleep at night so hence the MEGA doses of different benzos
2) Considered the pharmacokinetic interaction between modafinil + some benzo's, some clinical evidence to suggest it speeds up metabolism (hence probably why it helped me WAKE up so well in the morning
3) high dose benzo GABA-A + Modafinil mode of action in CNS = BAD
4) atypical reaction to modafinil
5) recently found out modafinil is a dopamine D2 partial D2, so placing bets on this factor being important

Interaction of some pro-drug opioids (codeine, dihydrocodeine)

On seperate recent occasions there seems to be a definite mental potentiation of codeine but even more so dihydrocodeine. Was taking the paramol tablets (i.e just 7.5mg od DHC!) and they were having a BIG effect

Reasons thus far explored:
1) modafinil induces CYP 1A2, 2B6, and 3A4 (explains many of benzo issues but trying to figure these one out - that just gets complicated!)

CYP3A4 responsible for codeine to norcodeine (no analgesic potential), thus leaving less codeine to be converted to fun compounds - so no go on that theory
CYP2B6 - explains the increased nicotine as known to be involved in nicotine metabolism but so far to my knowledge no effect on codeine/dihydrocodeine
CYP1A4 - ?no clues as to potential effect

2) Dopamine D2 partial agonism is synergistic with opioid intoxication
3) Mere mental simulation (I.e being awake) makes opioids more fun (upper downer theory)

Strange as in best ways to describe this feels like (especially with the low dose of dihydrocodeine 7.5mg) that effect is FAR more apparant than it should be. Wondering whether SOMETHING about enzyme inducing is increasing active metabolites.

BEFORE self experimentors try the combination it was noted that it had no effect on high doses

 

[longtimelurker]

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!

hi murphy. good to see you. i remember you from somewhere black.

i think you were thinking of piraceatam.

 

[longtimelurker]

my friend also bought some 'pure powder' from some well know place that deals in 'bulk'

of inferior quality to provigil and felt dirty according to him. i am yet to same this powder.

i took modalert before an had no problems with it.

 

[Silverfox]

Alone, maybe, but in combination with other stims (mostly cocaine, phenidate, and the like), many I know would beg to differ.

@PA can you elaborate? Modafinil has been used clinically to reduce cocaine dependance as it competes for the DA receptor and has a much longer half life. My personal experince is that I have far less fiending for coke if I have taken modafinil previously.

 

[phactor]

I really enjoyed Modafinil for the time I was on it, I was just restarting college after a few years of partying and whatnot. I have ADD but do not want to take amphetamines. Modafinil was able to help me focus and pull myself together until I was able to turn that into a habit.

Good stuff, worked great, didn't feel a thing (some jaw clenching the first few days), my appetite was okay and I was able to stop fine.

 

[Heuristic]

To throw in my .02:

I've used this for work purposes. 200mg has a tendency to give me a headache, and generally I used 100mg.

• From what I've heard/read, this is potentially quite useful for those with ADD/ADHD; but obviously that's something to discuss with your doctor.
  
• "Smart drug" issue: unless you actually have ADD/ADHD, this will have close to the same effect on your intelligence as any other substance marketed to make you temporarily smarter: marginal at best. However, if you're suffering from a cognitive deficit due to sleep deprivation, it will reduce the extent of the deficit (with close to the same effectiveness as caffeine).
  
• Still no long term studies: I'm a little wary due to this, since the lack of long term studies and the huge gaps in our knowledge about how this medication works and our brains add up to this: "we don't really know how or why, but modafinil has x positive effects; in the decade or so it's really been around, we haven't seen any negative effects other than y; if things go really badly in the future, we'll let you know."
  
• I view it as an occasionally useful substitute for coffee, especially if I'm so tired that the doses of caffeine I take will come with the usual negative side-effects.

 

[irobeth]

Of interest: Modafinil substitutes for caffeine when in withdrawal

If all goes well I can quit caffeine and then discontinue modafinil (why?) without many issues.


Is there a reason one would ever discontinue modafinil? Maybe blood pressure?
I use it periodically to daily and haven't noticed a permanent trend on the blood pressure -- if anything, it's gone down.

 

[MurphyClox]

I've used this for work purposes. 200mg has a tendency to give me a headache, and generally I used 100mg.

• From what I've heard/read, this is potentially quite useful for those with ADD/ADHD; but obviously that's something to discuss with your doctor.
  
• "Smart drug" issue: unless you actually have ADD/ADHD, this will have close to the same effect on your intelligence as any other substance marketed to make you temporarily smarter: marginal at best. However, if you're suffering from a cognitive deficit due to sleep deprivation, it will reduce the extent of the deficit (with close to the same effectiveness as caffeine).
  
• Still no long term studies: I'm a little wary due to this, since the lack of long term studies and the huge gaps in our knowledge about how this medication works and our brains add up to this: "we don't really know how or why, but modafinil has x positive effects; in the decade or so it's really been around, we haven't seen any negative effects other than y; if things go really badly in the future, we'll let you know."
  
• I view it as an occasionally useful substitute for coffee, especially if I'm so tired that the doses of caffeine I take will come with the usual negative side-effects.

That is the best short summary on this topic I've seen so far. Heuristic brings it down to a couple of lines.

- Murphy

 

[ebola?]

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

 

[P A]

@PA can you elaborate?

On a purely anecdotal basis, and at low-ish dosages that can't significantly occupy the catecholamine transporters, Provigil appears to be a decent potentiator of the so-called 'CNS stimulation' and euphoria subjectively perceived while under the influence of the better-known amphetamine and methylphenidate. [at least in my friends' experience(s); I have yet to try the cocktail myself]

 

[PsychedelicPeptide]

IMO Adrafinil is a pretty damn good product given its availability. I cannot compare to Modafinil but am happy with using Adra a few days a week.

I don't get excessive stimulant effects and can safely combine with caffeine or other nootropics, and I do find it slightly euphoric (especially when I first took it). It fits well with aniracetam which can help curb its ability to make one a bit erratic or prone to cursing (apparently this is the one main drawback to Moda) although after you take it a number of times I think you can get used to this effect and know to just let your mind relax. For some I can see this being a problem though.

One important note is that if you think you have bunk Moda/Adra you can always tell because the real stuff will make your urine smell different for the day. It should be a strong enough odor to where you notice it without having to put your head near the toilet, or at least I (with my good sense of smell) do.

Regarding the mechanism of action the wikipedia entry has a reference to a drug screen of modafinil against a "large panel of receptors and transporters" but the reference link is blank and I have not seen this work. But I have been looking into this subject on and off lately and there are probably multiple relevant sites of action, in addition to the two enantiomers having their own selectivity profiles. I wonder if in most of these clinical studies do the researchers know what enantiomer they are testing? The mixture (which modafinil is AFAIK) I suspect in most cases, especially older studies. But this will only add to confusion as both have their own profile and could mess with the delicacy of some of these experiments rendering their results subject to improper interpretation. ;-P

J Pharmacol Exp Ther. 2006 Nov;319(2):561-9.
Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro.

Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, Johnson R, Livni E, Spencer TJ, Bonab AA, Miller GM, Fischman AJ.

Department of Psychiatry, Harvard Medical School, New England Primate Research Center, 1 Pine Hill Dr., Southborough, MA 01772-9102, USA.

Abstract

2-[(Diphenylmethyl) sulfinyl]acetamide (modafinil), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by positron emission tomography imaging; in vitro, we determined modafinil activity at the DAT, NET, SERT, and rhesus monkey trace amine receptor 1 (TA1). In rhesus monkey, modafinil occupancy of striatal DAT was detected by [(11)C]2beta-carbomethoxy-3beta-4-(fluorophenyl)tropane and of thalamic NET by [(11)C](S,S)-2-(alpha-(2-methoxyphenoxy)-benzyl)morpholine. In vitro, modafinil effects in DAT-human embryonic kidney (HEK), NET-HEK, and SERT-HEK cells were investigated alone or combined with the TA1 receptor. Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12%, n = 4; 8 mg/kg: 54 +/- 3%, n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.8%, n = 6; 8 mg/kg: 44 +/- 12%; n = 2). In vitro, modafinil inhibited [(3)H]dopamine (IC(50) = 6.4 microM), [(3)H]norepinephrine (IC(50) = 35.6 microM), and [(3)H]serotonin (IC(50) > 500 microM) transport via the human DAT, NET, and SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but it augmented a monoamine transporter-dependent enhancement of phenethylamine activation of TA1 in TA1-DAT and TA1-NET cells, but not in TA1-SERT cells. The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.

Synapse. 2009 Aug;63(8):698-704.
Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil.

Seeman P, Guan HC, Hirbec H.

Department of Pharmacology, Medical Science Building, University of Toronto, Toronto, Ontario, Canada.

Abstract

Although it is commonly stated that phencyclidine is an antagonist at ionotropic glutamate receptors, there has been little measure of its potency on other receptors in brain tissue. Although we previously reported that phencyclidine stimulated cloned-dopamine D2Long and D2Short receptors, others reported that phencyclidine did not stimulate D2 receptors in homogenates of rat brain striatum. This study, therefore, examined whether phencyclidine and other hallucinogens and psychostimulants could stimulate the incorporation of [(35)S]GTP-gamma-S into D2 receptors in homogenates of rat brain striatum, using the same conditions as previously used to study the cloned D2 receptors. Using 10 microM dopamine to define 100% stimulation, phencyclidine elicited a maximum incorporation of 46% in rat striata, with a half-maximum concentration of 70 nM for phencyclidine, when compared with 80 nM for dopamine, 89 nM for salvinorin A (48 nM for D2Long), 105 nM for lysergic acid diethylamide (LSD), 120 nM for R-modafinil, 710 nM for dizocilpine, 1030 nM for ketamine, and >10,000 nM for S-modafinil. These compounds also inhibited the binding of the D2-selective ligand [(3)H]domperidone. The incorporation was inhibited by the presence of 200 microM guanylylimidodiphosphate and also by D2 blockade, using 10 microM S-sulpiride, but not by D1 blockade with 10 microM SCH23390. Hypertonic buffer containing 150 mM NaCl inhibited the stimulation by phencyclidine, which may explain negative results by others. It is concluded that phencyclidine and other psychostimulants and hallucinogens can stimulate dopamine D2 receptors at concentrations related to their behavioral actions.

JAMA. 2009 Mar 18;301(11):1148-54.
Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications.

Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, Wang GJ, Jayne M, Hooker JM, Wong C, Hubbard B, Carter P, Warner D, King P, Shea C, Xu Y, Muench L, Apelskog-Torres K.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Abstract

CONTEXT: Modafinil, a wake-promoting drug used to treat narcolepsy, is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise. OBJECTIVE: To measure the acute effects of modafinil at doses used therapeutically (200 mg and 400 mg given orally) on extracellular dopamine and on dopamine transporters in the male human brain. DESIGN, SETTING, AND PARTICIPANTS: Positron emission tomography with [(11)C]raclopride (D(2)/D(3) radioligand sensitive to changes in endogenous dopamine) and [(11)C]cocaine (dopamine transporter radioligand) was used to measure the effects of modafinil on extracellular dopamine and on dopamine transporters in 10 healthy male participants. The study took place over an 8-month period (2007-2008) at Brookhaven National Laboratory. MAIN OUTCOME MEASURES: Primary outcomes were changes in dopamine D(2)/D(3) receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo. RESULTS: Modafinil decreased mean (SD) [(11)C]raclopride binding potential in caudate (6.1% [6.5%]; 95% confidence interval [CI], 1.5% to 10.8%; P = .02), putamen (6.7% [4.9%]; 95% CI, 3.2% to 10.3%; P = .002), and nucleus accumbens (19.4% [20%]; 95% CI, 5% to 35%; P = .02), reflecting increases in extracellular dopamine. Modafinil also decreased [(11)C]cocaine binding potential in caudate (53.8% [13.8%]; 95% CI, 43.9% to 63.6%; P < .001), putamen (47.2% [11.4%]; 95% CI, 39.1% to 55.4%; P < .001), and nucleus accumbens (39.3% [10%]; 95% CI, 30% to 49%; P = .001), reflecting occupancy of dopamine transporters. CONCLUSIONS: In this pilot study, modafinil blocked dopamine transporters and increased dopamine in the human brain (including the nucleus accumbens). Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse, and considering the increasing use of modafinil, these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations.

A follow-up to their last statement...

The lack of modafinil abuse also highlights the need for heightened awareness for an increased understanding of how different molecules can stimulate the same systems but produce significantly different results. =)