What is the mechanism behind not feeling tired on Amphetamines?

[DexWeedAndMe]

Ok, so I'm about as aware as someone (who's not one of the ridiculously-insane substance geniuses of BL's AD section) can be on how amphetamines work. By reversing the action of the dopamine transporters (DAT), they cause an efflux of dopamine (DA). They also prevent the reuptake of DA. These factors result in an increased concentration of extracellular DA. They also do the same for norepinepherine and serotonin (though to lesser degrees, I presume).

Now, pretty much anyone among the "drug nerd" circle knows that amphetamines diminish tiredness. Though they may not necessarily eliminate the need for sleep (hence people having delirious hallucinations after a multi-day amphetamine binge). I'm just interested to know how exactly this works. I presume it has something to do with the actions of the neurotransmitters, however, I read about, and study, drugs.. not sleep. I couldn't tell you the first thing about what causes one to be tired, aside from simply being tired. So I figured I'd come to AD and ask those more knowledgeable about these matters exactly how this works. I appreciate anyone who takes the time to respond.

 

[lovegluegunnin]

hey, Dex. I can't send any more messages so I hope you don't mind me posting in this as a means of replying lol. I like both Indica strains and Sativa strains. If I'm bored or wanting to have some fun, I prefer a Sativa strain so I can get giggly and energetic. But If I'm depressed or just wanting to chill or sleep, I'll take an Indica strain. Mostly because when I'm depressed or in a low wave (I'm bipolar-schizophrenic and suffer from ADHD), nothing really stops it but a good cry and some sleep.

Addies - I looove amphetamines, but I would never touch meth, or ice or any variation of the sort. I take some adderall before I go to school and I get allll the shit done lol. Then once I get home and I see my dad, I'm actually happy to see him for a change in spite of all the shit he's put me, my mother and my twin brother through. The only thing I don't like about adderall and vyvanse is that I tend to grind my teeth and bite my tongue a lot when I'm on them.

Cigarettes - I'm not a very heavy smoker, however, I do love my ciggies. I like marlboro reds, or as my family lovingly refers to them as, "Cowboys." I like smoking after meals, when I first wake up, before I go to bed, or just because. I try and limit my niccotene (sp?) intake as much as possible, though. I smoke maybe half a pack a day. Hopefully, the amount I smoke will become smaller and smaller.

Music - OH man, you are awesome so far lol. I love Metallica, Def Leppard, Johnny Cash, and Pink Floyd, so we have that in common. My current favorite band is Brand New, however a couple of other fave artists and bands are Led Zeppelin, The Beatles, Nirvana, Hole, Lana Del Rey, Lady Gaga, Kendrick Lamar and the others in the group Black Hippy, J. Cole, etc.

 

[Captain.Heroin]

The norepinephrine builds up; tolerance to dopamine/serotonin accumulates quicker.

With continued usage, you just get stimulation and the sense of euphoria wears thin.

 

[DexWeedAndMe]

Love, ahhh that's right. Greenlighters can't PM. Forgot about that. I believe you change to a Bluelighter after 50 posts.

I feel you on the crank and such. I couldn't see myself getting too up on those. I mean, more power to those who enjoy 'em, but.. I'm cool with just adds. Generally most stimulants tend to have that side-effect. I know MDMA and Methylone in particular make me clinch like a mf'er. I feel that though, reds are pretty nice. Generally anything but menthols is cool (Newports aside. Newports rock.)

Hell yeah, well it sounds as though you have quite the musical taste. I like.
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Now, back on topic...
Appreciate the answer Captain H. So, is norepinephrine depletion what causes tiredness in the firse place? Also, I knew that as tolerance was built, it tended to become mostly stimulation. Is it a downregulation in the Serotonin and Dopamine receptors which causes the loss of euphoria?

 

[lovegluegunnin]

Love, ahhh that's right. Greenlighters can't PM. Forgot about that. I believe you change to a Bluelighter after 50 posts.

I feel you on the crank and such. I couldn't see myself getting too up on those. I mean, more power to those who enjoy 'em, but.. I'm cool with just adds. Generally most stimulants tend to have that side-effect. I know MDMA and Methylone in particular make me clinch like a mf'er. I feel that though, reds are pretty nice. Generally anything but menthols is cool (Newports aside. Newports rock.)

Hell yeah, well it sounds as though you have quite the musical taste. I like.
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Now, back on topic...
Appreciate the answer Captain H. So, is norepinephrine depletion what causes tiredness in the firse place? Also, I knew that as tolerance was built, it tended to become mostly stimulation. Is it a downregulation in the Serotonin and Dopamine receptors which causes the loss of euphoria?

Oh, well that's not too far away for me, then. Lol I just started posting tonight and I'm already up to 30 posts. That's where addies get me.

As I said before in a separate thread that I forget the name of, my step dad used to do pretty potent kinds of Ice several times a day and quit it cold turkey, but I don't think I would be that fortunate if I ever tried it. I think I'll just stick to what's prescribed to me, as well as my cigarettes and marijuana. Do you like Marijuana? If so, what's your favorite strain?

 

[JWills20]

Tiredness and sleeping is primarily modulated by the sleep-wake cycle, of which I believe is primarily mediated by serotonin-melatonin fluctuation. Because the brain is saturated with extracellular concentrations of DA/NE & (to a lesser extent) 5HT, the natural conversion of 5HT into melatonin is inhibited. Further, NE especially causes peripheral stimulation further promoting wakefulness. It's all to do with the overall neurochemical balance of the brain. If DA/NE exceeds 5HT (as is the case with usual amphetamines), you feel stimulated, hyperactive, euphoric and energetic. Conversely, with MDMA the high selectivity for serotonin can cause the opposite effect. That is, as dosage increases as does the 5HT: DA/NE ratio because MDMA is specifically selective to 5HT and only partially for DA/NE. Thus, higher doses can induce feelings of relaxation, contentness and an overall feeling of well-being with the world. This is my theory for why people report feeling 'floored' from MDMA. I have even heard that one person fell asleep during an MDMA peak, which is kind of astonishing considering that it is still a stimulant by definition.

 

[Grand Touring]

The norepinephrine builds up; tolerance to dopamine/serotonin accumulates quicker.

With continued usage, you just get stimulation and the sense of euphoria wears thin.

Downregulating the dopamine receptors stimulates the frontal lobes (hyperfrontality) which controls everything from decision making to consciousness.

 

[pofacedhoe]

monoamine releasers like amphetamine keep you awake by releasing lots of dopamine and noradrenaline. noradrenaline is the important bit

noradrenergic drugs will wake you up. eg iv noradrenaline at a high level might wake you up from a very low level propofol infusion.

fight or flight=awake

 

[endotropic]

^ and an adrenaline filled needle to the heart will rouse Mia Wallace from a heroin overdose.

My hunch is you're 100% correct regarding norepinephrine as the primary culprit, I'm having trouble finding literature to back that up though.

 

[sekio]

I recall hearing somewhere that brain histamine levels play a large role in wakefulness (c.f. antihistamines as sleep aids) and that modafinil derives some of its wakefulness promoting actions by stimulating histamine release.

I can also say with some certainty that elevated levels of NE aren't really stimulating as much as they are outright unpleasant. For me and many people I know, atomoxetine - the only NRI around, really - was about as much fun as the flu.

Also of note is that N-ethylcathinone is a plain norepinephrine releaser; I wonder if it too is a wakefulness promoter (and how much of its activity comes from downstream metabolism into "plain" cathinone)

 

[ebola?]

Also of note is that N-ethylcathinone is a plain norepinephrine releaser; I wonder if it too is a wakefulness promoter (and how much of its activity comes from downstream metabolism into "plain" cathinone)

Trip reports show that it rather clearly is. Also, given the relatively small amount of methamphetamine catabolized to amphetamine in vivo, i wouldn't expect cathinone to explain much of its activity.

ebola

 

[ebola?]

Also, to further speak to the OP's question, we'd want to examine the downstream activity seen following NE and DA release. With DA release, you have stimulation of the mesolimbic reward pathway, which is linked to increased 'seeking' activity. You also have stimulation of frontal cortical areas, increasing top-down modulation associated with 'executive' type cognitive activity, which is also not associated with tiredness. You also have NE release stimulating hindbrain areas, creating a general sense of alertness and arousal when oriented toward stimuli. You also have NE causing increased amygdalic activity that correlates with strong emotional arousal (often resembling fear, but not in the case of the experience on stimulants...there, it's more general arousal.

ebola

 

[Lightning-Nl]

I recall hearing somewhere that brain histamine levels play a large role in wakefulness (c.f. antihistamines as sleep aids) and that modafinil derives some of its wakefulness promoting actions by stimulating histamine release.

Pretty much my understanding. Some good information on this subject was the research they've done into H3 and H4 antagonists. However, H3 and to a lesser extend H4 antagonism appears to upramp Glutamate release, as well as downramp Serotonin and Norepinephrine, and possibly upramp Dopamine release. I can't do the subject justice through a simple explanation. However, I feel that saying Histamine is the cause of what causes you to feel awake is a little too over simplified.

I think a better way to summarize the subject is - Histamine is stimulating at different receptors and different neurons. In the case of H1 agonism - Histamine binding causes stimulation, which is why drugs like Diphenhydramine cause sedation when ingested.

I can also say with some certainty that elevated levels of NE aren't really stimulating as much as they are outright unpleasant. For me and many people I know, atomoxetine - the only NRI around, really - was about as much fun as the flu.

Yes - very much so. Elevated Norepinephrine is like being wired without any of the euphoria. It's not recreational and not unlike being in a state of intense panic. On a side note, however, atomoxetine has some slight affinity for DAT. It's not much, but it exists.

Also of note is that N-ethylcathinone is a plain norepinephrine releaser; I wonder if it too is a wakefulness promoter (and how much of its activity comes from downstream metabolism into "plain" cathinone)

Another good example of an NRA/NRI is Ephedrine. Ephedrine has DAT affinity as well, but it's 1/18th that of it's NE affinity. Which is probably why it only seems to precipitate a panic attack whenever I try to abuse it. But, it's worth noting none-the-less.

Also it's important to note that DA/NE release (in combination) is very important for why NDRI/NDRA's are very psychologically reinforcing. Dopamine release by itself - while reinforcing isn't necessarily addicting in the same sense as DA/NE release. Same goes for NE release. By itself, it's not necessarily addicting or even that pleasant. It's the combination of the two that causes the reinforcing addictive nature of conventional stimulants.