How is amphetamine neurotoxic? What does it do to you?

[DuckTheQuackerRC]

There is 1000 different amphetamines.
Caffeine harms more then pure amfet coocked by pro.
No need in fat lines, 5 - 10 mg mountain will do to fuck ur girlfriend or wife for good 5- 10 hours... similar to coke
Know lots of people used to do it, most still do invisibly. Still alive, got healthy kids.

Of cos if its dirty bridgwater amfet coockewd by tramp in a bush, who watched youtube in public library and learned to coock meth through tutorials.
There will be lots of side effects!

Or if some one dosing u with it, and u on it for weeks with out sleep going schizophrenic.
Not cos of amfet, cos of a sandwich of different RC substances.

Another side efect many rats starting to fuck each other in da ass ! What causes hemoroids or piles of long time fucking.

Baked & Salted

 

[sekio]

Caffeine harms more then pure amfet coocked by pro.

Somehow I doubt this. Caffeine's LD50 is 127 mg/kg oral in mouse, and amphetamine is 21 mg/kg.

 

[Xorkoth]

LD50 isn't everything, yet I also doubt very much that caffeine is less toxic than amphetamine (or methamphetamine as you seem to be suggested you're talking about). I have never heard of anyone having health problems from daily dosing of caffeine, even rather high doses, unless they have pre-existing heart problems or something.

 

[AlphaMethylPhenyl]

Somehow I doubt this. Caffeine's LD50 is 127 mg/kg oral in mouse, and amphetamine is 21 mg/kg.

Fine. But you really love caffeine too much. Just because it has a fairly long honeymoon period and is legal/less dangerous than many other drugs doesn't make it a panacea and certainly doesn't take away from its inferior subjective effects relative to pretty much any other mildly psychoactive drug. That ceiling effect is a bitch too.

 

[endotropic]

Fine. But you really love caffeine too much. Just because it has a fairly long honeymoon period and is legal/less dangerous than many other drugs doesn't make it a panacea and certainly doesn't take away from its inferior subjective effects relative to pretty much any other mildly psychoactive drug. That ceiling effect is a bitch too.

Its unparalleled safety and mild effects are exactly what make caffeine so special and useful.

 

[Seppi]

There is 1000 different amphetamines.
Caffeine harms more then pure amfet coocked by pro.
No need in fat lines, 5 - 10 mg mountain will do to fuck ur girlfriend or wife for good 5- 10 hours... similar to coke
Know lots of people used to do it, most still do invisibly. Still alive, got healthy kids.

Of cos if its dirty bridgwater amfet coockewd by tramp in a bush, who watched youtube in public library and learned to coock meth through tutorials.
There will be lots of side effects!

Or if some one dosing u with it, and u on it for weeks with out sleep going schizophrenic.
Not cos of amfet, cos of a sandwich of different RC substances.

Another side efect many rats starting to fuck each other in da ass ! What causes hemoroids or piles of long time fucking.

Baked & Salted

This is the most eloquent and articulate prose I've ever read. :O

 

[BlueHues]

^English isn't everyone's first language...I think he conveyed the points he was trying to cover quite adeptly!

Do rats really fuck each other in the ass on speed?

 

[BallsStapledToLeg]

No, you read it correctly, but you're not seeing through the authors' bullshit. Compare fig. 4. with what the metabolism section says about amphetamine. You'll then wonder why they chose to included alpha-methyldopamine (shown as 3,4-dihydroxyamphetamine) as a metabolite in that graphic. That is one of the highly neurotoxic metabolites in other species.

Human CYP2D6 and FMO3 are responsible for 4-hydroxylations in the human metabolic pathway. These DO NOT 3-hydroxylate any metabolites in humans. Hence, humans DO NOT produce any 3,4- (catechol type) metabolites. Read the papers they cite on hydroxylation. You could also read the refs in the amphetamine pharmacokinetics section and you'll see that neither their references nor my references state that humans produce 3-hydroxy metabolites from amphetamine.

I couldn't find anything saying humans produced significant quantities of alpha-methyldopamine from (meth)amphetamine either, though I'm not quite sure what significance this has to your assertion that its majorly responsible for the inter-species difference in neurotoxicity. It's fairly benign in rats, which is where a lot of the inter-species differences claims come from http://www.ncbi.nlm.nih.gov/pubmed/1860050. Now I might be missing a study that shows it destroys monkeys, but I don't follow your logic saying that metabolism of (meth)amphetamine into 3,4-dihydroxyl products is a major determinant of inter species vulnerability. MDMA we can both agree is going to have a lot of species variance with metabolism and is likely going to be effected by this, but I still don't understand exactly what you're getting at here.

The whole cardiotoxicity section contradicts the massive FDA studies on the lack of cardiac effects in amphetamine at therapeutic doses (see amphetamine - side effects section). The FDA sample was practically a census (literally, massive, and afaik included 100% of the target population for statistical inference in the sample). They used case reports (imo: ROFL...anecdotal evidence) to argue their point that amphetamine is has severe cardiac adverse effects at therapeutic doses.

.
Stimulant and stress induced arrhythmias and cardiomyopathies are commonly acknowledged adverse effects, I think the author is just cherry picked data to show that it can happen at therapeutic doses. Increased cortisol + the handful of other stress response hormones + vasoconstriction/hypertension + increased cardiac work load= occasional cardiac issues. I'm willing to bet that a substantial number of these cases had undiagnosed cardiac conduction issues or other risk factors. What a researcher can rant about "risk of severe cardiac events" the FDA will pretty much reply "Do not use if you have... If you experience... Call your doctor right away". Shitty evidence is shitty, but its nothing too out of the blue as far as I can see.

The sentence below is flat out wrong since FMO3 is just as dominant (conditionally, more dominant) as CYP2D6 metabolism in humans. The review doesn't even mention FMO3 or DBH. But, it mentions GSH conjugates which have never been observed in humans.
Since, in humans, amphetamines are mainly metabolized
by the enzymatic complex CYP450, their effects can be
influenced by PK/PD interactions with other compounds
(pharmaceuticals, drugs of abuse, nutrients, etc.) that share
or affect the same metabolic pathway (Oesterheld et al.
2004).

Toxnet/pubchem (basically, NCBI) indicates w/ multiple monographs on both pages (link to HSDB/Toxnet) that there is a LOT of interspecies variability in metabolism.

Not going to argue much here, its kind of a weird mash up of human and animal data. Didn't really give me as much as I would have liked on the toxic metabolite theory you're pitching. Interesting reading nonetheless

I have no clue how this paper passed peer review. I'd have forced them to fix their shit if I reviewed it, which is sad because I'm not even a researcher in their field; yet, I can spot glaring errors or misleading statements on every page with text.

It does have some issues, but I still don't see where your metabolite theory comes from. I can understand that differences in metabolism are frequently implicated in the different toxicity levels across species. But, I haven't seen anything specific to humans that applies to (meth)amphetamine that really strikes me as a smoking gun.

Researchers that use the term "amphetamines" to refer to anything but amphetamine also annoy me since it's an abuse of language.

Agreed it makes searching for anything a nightmare 8(

In any event, the part of the review on indirect neurotoxicity in amph is actually correct - it involves DA autoxidation and ROS production in humans. That's why I cited it. The rest is crap - I personally believe these authors, instead of simply being crappy researchers, just have an agenda to trash these drugs.
I can't imagine why else there isn't a single positive or differentiating factor mentioned for amphetamine in humans from subst. amphetamines in humans OR amphetamine in other animals. These aren't obscure facts; Pubchem or Toxnet/HSDB alone differentiates amphetamine in humans and other animals completely (see animal monologues). They even states there is likely no direct toxicity in humans, differentiating it from other subst. amphs (see human monologues).

I think its pretty well accepted that most if not all of (meth)amphetamine's neurotoxic actions stem from indirect damage. The issue I'm arguing is that we don't have a good measure for when amphetamine neurotoxicity begins in humans, we can all agree if its used responsibly and only at theraputic doses the damage is likely minimal. However, that doesn't mean harm reduction strategies aren't valid.

If you could detail exactly how (meth)amphetamine produces toxic metabolites in other primates or rodents but not humans I'd be very interested in hearing it! I don't mean to seem like I'm ragging on you, but I'd really like to see what you're getting at. Personally I'm more in the camp that differences in TAAR affinity or differences in responses to ROS are likely to be responsible for the noted inter species differences.

 

[Seppi]

I couldn't find anything saying humans produced significant quantities of alpha-methyldopamine from (meth)amphetamine either, though I'm not quite sure what significance this has to your assertion that its majorly responsible for the inter-species difference in neurotoxicity. It's fairly benign in rats, which is where a lot of the inter-species differences claims come from http://www.ncbi.nlm.nih.gov/pubmed/1860050. Now I might be missing a study that shows it destroys monkeys, but I don't follow your logic saying that metabolism of (meth)amphetamine into 3,4-dihydroxyl products is a major determinant of inter species vulnerability. MDMA we can both agree is going to have a lot of species variance with metabolism and is likely going to be effected by this, but I still don't understand exactly what you're getting at here.

AAAH is the only enzyme in our metabolic repertoire with the capacity to 3-hydroxylate these types of compounds (endogenous/exogenous PEA's). Human AAAH doesn't act on amph. This means AMDopa isn't a metabolite; that in turn implies its quinones and GSH conjugates are not metabolites. That's all I'm asserting here. This link goes over neurotoxicity research of AMDopa & its metabolites.
I didn't mean to suggest that this is the reason for the differences seen in rats vs humans as much as a possible and "reasonable explanation" for it. Metabolites may have nothing to do with interspecies variations in toxicity at all - it could come entirely from pharmacodynamic differences.

Stimulant and stress induced arrhythmias and cardiomyopathies are commonly acknowledged adverse effects, I think the author is just cherry picked data to show that it can happen at therapeutic doses. Increased cortisol + the handful of other stress response hormones + vasoconstriction/hypertension + increased cardiac work load= occasional cardiac issues. I'm willing to bet that a substantial number of these cases had undiagnosed cardiac conduction issues or other risk factors. What a researcher can rant about "risk of severe cardiac events" the FDA will pretty much reply "Do not use if you have... If you experience... Call your doctor right away". Shitty evidence is shitty, but its nothing too out of the blue as far as I can see.

I agree with your premise and conclusion provided it's a single case. When I read a paper and think "WTF?" in several sections though, there's a problem. I'd let this section slide if the rest of the paper were written in a neutral, balanced point of view. Unfortunately, it's not.

I think its pretty well accepted that most if not all of (meth)amphetamine's neurotoxic actions stem from indirect damage. The issue I'm arguing is that we don't have a good measure for when amphetamine neurotoxicity begins in humans, we can all agree if its used responsibly and only at theraputic doses the damage is likely minimal. However, that doesn't mean harm reduction strategies aren't valid.

If you could detail exactly how (meth)amphetamine produces toxic metabolites in other primates or rodents but not humans I'd be very interested in hearing it! I don't mean to seem like I'm ragging on you, but I'd really like to see what you're getting at. Personally I'm more in the camp that differences in TAAR affinity or differences in responses to ROS are likely to be responsible for the noted inter species differences.

There is a large amount of clinical evidence that meth is neurotoxic in humans. There's two reviews out there asserting that sigma receptors play an important role in mediating its neurotoxic effects. (I already linked these)
There's a large amount of clinical evidence that amphetamine (permanently) restores/improves areas of brain function and structural abnormalities in those with ADHD.*** Another review I cited earlier stated that there's increased transporter availability seen in those who use amphetamine at therapeutic doses (this is the reverse case of neurotoxicity). So, in a nutshell, if there's some neurotoxic component to amphetamine when used at therapeutic doses, it's a triviality and not a cause for concern because its effect don't manifest clinically in humans.

So, I haven't been trying to argue that it's not neurotoxic. These papers have already shown that it's not, and even further provided evidence of it being a neurogenerative or neuroprotective compound (depends upon what causes the reductions in size for people with ADHD). Since these are reviews and meta-analyses of human data, this is high quality clinical evidence supporting these points. Everything else is just me been postulating why we see differences between species/compounds.




*** I'm too lazy to remove the wikitext. Just pull the "pmid=" value and search pubmed with it.
<ref name="Neuroplasticity 1">{{cite journal |author=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K |title=Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects |journal=JAMA Psychiatry |volume=70 |issue=2 |pages=185–198 |date=February 2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277 |url=}}</ref>
<ref name="Neuroplasticity 2">{{cite journal |author=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J |title=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies |journal=J. Clin. Psychiatry |volume=74 |issue=9 |pages=902–917 |date=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |url= |pmc=3801446}}</ref>
<ref name="Neuroplasticity 3">{{cite journal | title=Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. | journal=Acta psychiatrica Scand. | date=February 2012 | volume=125 | issue=2 | pages=114–126 | pmid=22118249 | author=Frodl T, Skokauskas N | quote=Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.}}</ref>

 

[Seppi]

^English isn't everyone's first language...I think he conveyed the points he was trying to cover quite adeptly!

Do rats really fuck each other in the ass on speed?

I think rats have it so bad with amphetamine you could probably make them do anything under the right conditions. But ya, they can show sexual compulsion just like abuse of amph/meth as an aphrodisiac can in humans.

 

[Dresden]

Well, maybe those particular enzymes don't 3-hydroxylate in humans, but something sure must, otherwise the body would never be able to synthesize dopamine (3,4-dihydroxyphenylethylamine) from tyrosine?

Also, here's another question for you drug nerd experts: I have taken 360 mg of Adderall IR over the past 18 hours. Do I need to worry about neurotoxicity or should I be worrying more about my cardiovascular health due to this admitted binging of amphetamine?

Thanks in advance.

 

[BallsStapledToLeg]

Well, maybe those particular enzymes don't 3-hydroxylate in humans, but something sure must, otherwise the body would never be able to synthesize dopamine (3,4-dihydroxyphenylethylamine) from tyrosine?

Also, here's another question for you drug nerd experts: I have taken 360 mg of Adderall IR over the past 18 hours. Do I need to worry about neurotoxicity or should I be worrying more about my cardiovascular health due to this admitted binging of amphetamine?

Thanks in advance.

You might want to invest in some lipid soluble antioxidants, that is a hefty dose right there.

Tyrosine hydroxylase to the best of my knowledge is the enzyme you're talking about. Fairly sure amphetamine and its common metabolites aren't good substrate for it

 

[Trying2Iso]

Amphetamine is not neurotoxic
But Staying up for 5 days is.

 

[Dresden]

If amphetamines are not a good substrate for tyrosine hydroxylase, then why does a google search of "N-propylamphetamine metabolites" indicate that N-propylamphetamine is metabolized to 4-hydroxy-3-methoxy-N-propylamphetamine?

 

[AlphaMethylPhenyl]

Amphetamine is not neurotoxic
But Staying up for 5 days is.

This is the most common mistake (or forgetfulness of not adjusting for confounding factors) in these studies.

 

[sekio]

If amphetamines are not a good substrate for tyrosine hydroxylase, then why does a google search of "N-propylamphetamine metabolites" indicate that N-propylamphetamine is metabolized to 4-hydroxy-3-methoxy-N-propylamphetamine?

just because a metabolite is present doesn't mean it's the major one. I thought most amphetamine was excreted unchanged, and a small amount deaminated to phenylacetone/phenylacetic acid.

 

[Lost Ego]

Imagine your brain as a billion little engines. Now rev a group of the engines to 10,000 rpm and what happens? They explode. This makes a nice little mess in that portion of your brain.

[Your brain also has cells called astrocytes. Their job is the janitor - they go around cleaning and removing any foreign materials.] The astrocytes find the mess in your brain and think it's an intruder. They try to spray down the 'intruder' with chemicals and instead kill the surrounding neurons, causing them to explode and make a bigger mess. This causes the "cascade of death" and kills many neurons.

amphetamines themselves are not neurotoxic but the way the affect neurons is detrimental to the health of your brain.

sources: an intro to neuroscience class & an intro to psychopharmocology class. i made up the analagy, they did not.

 

[Lightning-Nl]

Imagine your brain as a billion little engines. Now rev a group of the engines to 10,000 rpm and what happens? They explode. This makes a nice little mess in that portion of your brain.

[Your brain also has cells called astrocytes. Their job is the janitor - they go around cleaning and removing any foreign materials.] The astrocytes find the mess in your brain and think it's an intruder. They try to spray down the 'intruder' with chemicals and instead kill the surrounding neurons, causing them to explode and make a bigger mess. This causes the "cascade of death" and kills many neurons.

amphetamines themselves are not neurotoxic but the way the affect neurons is detrimental to the health of your brain.

sources: an intro to neuroscience class & an intro to psychopharmocology class. i made up the analagy, they did not.

This happens only at doses way beyond therapeutic indications. Proper, medical usage of amphetamine will not result in any of the above happening. Studies have proven this.

In fact, there is also a large amount of evidence showing that therapeutic usage of amphetamine and methylphenidate (specifically) actually corrects brain abnormalities and disregularities.

 

[Noodle473]

responsible drug use will lead to a new world order : Utopia.

 

[AlphaMethylPhenyl]

This happens only at doses way beyond therapeutic indications. Proper, medical usage of amphetamine will not result in any of the above happening. Studies have proven this.

In fact, there is also a large amount of evidence showing that therapeutic usage of amphetamine and methylphenidate (specifically) actually corrects brain abnormalities and disregularities.

Source?