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

[Seppi]

Dopamine that has been metabolized by MAO B into DOPAC (Dihydroxyphenylacetic Acid) is itself neurotoxic, especially with depleted glutathione, SOD or methyl donors. One of the hypotheses of late onset Parkinson's disease may be related to oxidative cellular injury from years of dopamine metabolites wreaking havoc in the substantia nigra and mesolimbic pathways, & if antioxidants are depleted, any dopamine reuptake inhibitor or releaser can have this effect. As to whether or not this is the only neurotoxicity associated with methamphetamine is not known. But low dose methamphetamine or methamphetamine use with adequate antioxidants does not appear to be significantly neurotoxic in a 6-OH DA sense like MPP+.

Fair point, although that is still just indirect/threshold neurotoxicity; every substance (example: water/salt) causes such a toxicity, e.g., fluid overload vs salt overload (or toxicities, such as a catastrophic complication from treating fluid overload), even if only at an extreme dose or in unusual circumstances.

 

[ebola?]

The problem with methylated amphetamines isn't necessarily the stimulation of the adrenergic receptors, but the type of adrenergic receptors selected for... meth prefers the adrenergic receptors increasing your heart's output and contractility (pumping strength), all while constricting the peripheral arterioles.

This is incorrect, as meth exerts less direct adrenergic activity than amphetamine and is also less selective for release of NE.

Fair point, although that is still just indirect/threshold neurotoxicity

While indirect, the neurotoxic mechanism is still highly relevant. Hell, this type of neurotoxicity occurs in the normal process of aging, albeit at a drastically reduced rate.

every substance (example: water/salt) causes such a toxicity, e.g., fluid overload vs salt overload (or toxicities, such as a catastrophic complication from treating fluid overload), even if only at an extreme dose or in unusual circumstances.

This analogy is irrelevant, as people often take large doses of stimulants, but not water or salt.

ebola

 

[21p]

...Did you even read what I wrote before you posted that? [/URL]

Maybe you should review your medical terminology before laying someone low, ace. Re-read what I wrote and holler back.

Amphetamine isn't a neurotoxin at therapeutic doses - it's neurogenerative, since it *INCREASES* DAT availability and gray cortical matter volume at lower doses - entirely opposite to the "weak neurotoxicity" that I stated exists for harsh long-term abuse directly above.
References:
Lack of neurotoxicity: PMID 17606768 (a review on humans) "Imaging studies of ADHD-diagnosed individuals show an increase in striatal dopamine transporter availability that may be reduced by methylphenidate treatment."
Presence of neurogenesis: I really don't feel like re-stating what I wrote here. Just read the first paragraph of the medical section.

As for the research you posted... here is the conclusion summary from "Imaging studies..."

CONCLUSION:
Clarification of the neurological consequences of chronic AMPH treatment for ADHD is needed.

Don't browse a paper and spit it out as evidence unless you're prepared to defend it. Your brain normally upregulates transporter systems being used, which means changes in the mass and density of the brain will naturally take place upon use of psychoactive drugs. The authors noted 'trophic' growth, which indicates the type of growth is not yet understood (as of 2007). By definition, this means it cannot be labelled 'neuroprotective' until further studies are done. Neuroplastic? possibly.

Hate to be a jerk, but your research is weak sauce and shouldn't be cited as evidence of anything other than what is stated in the text.

This is incorrect, as meth exerts less direct adrenergic activity than amphetamine and is also less selective for release of NE.



While indirect, the neurotoxic mechanism is still highly relevant. Hell, this type of neurotoxicity occurs in the normal process of aging, albeit at a drastically reduced rate.



This analogy is irrelevant, as people often take large doses of stimulants, but not water or salt.

ebola

I appreciate the repsonse. NE/Epi selectivity is a gradient, not either/or. You may have more B1 receptors in your heart, but it doesn't mean the rest are missing. You also have to take into account potency and rapid de/re-methylation occurring in the liver when ingesting meth. Meth doubles down on the CNS and PNS easily relative to amps, although you are partially correct about the receptor selectivity.

 

[ebola?]

Your brain normally upregulates transporter systems being used, which means changes in the mass and density of the brain will naturally take place upon use of psychoactive drugs.

Transporters are complexes of a few macromolecules and contribute little to overall brain mass.

NE/Epi selectivity is a gradient, not either/or.

This is correct, but doesn't really address my point (in fact, it was implicit in my first point).

You may have more B1 receptors in your heart, but it doesn't mean the rest are missing.

Could you please clarify? I'm not really understanding what you mean by this or how it applies.

You also have to take into account potency and rapid de/re-methylation occurring in the liver when ingesting meth.

Hepatic demethylation of methamphetamine is comparatively sluggish and applies to only a small proportion of its metabolism (in fact, most is excreted unchanged).

Meth doubles down on the CNS and PNS easily relative to amps

I don't quite understand what you mean. Are you saying that meth exerts greater (nor)adrenergic effects because it is more potent, so the dosages are effectively higher? It really makes more sense to compare across stimulants in terms of equistimulating doses.

you are partially correct about the receptor selectivity.

I'd indeed like to know where I was mistaken.

ebola

 

[21p]

I'd indeed like to know where I was mistaken.

I'm not saying you are way off. I think your model may just need a bit of tuning. Are you familiar with the different adrenergic receptor classes and which areas they're found in the body? Meth and amp stimulate the release of proportionally different NE/E ratios, but the location of those adrenergic receptors varies quite a bit from person to person. The effects of NE overlap with Epi both by location of A1,B1,A2,B2 receptors and by actual physiological response to ligand binding. Amp tolerance varies widely... this is why.

Check out a comparative graph of NE/E/Dopa and you'll see the effects would only be pronounced if one of the counter-balancing adrenergic receptors (A2) was missing or other substances were involved. You'll see what I mean.

The demethylation of meth mech was switched around in my head. I'd forgotten it was an inducer... cleavage results in clearance/d/l amp. I'd argue an equistimulating dose of amp will be tough to recreate because of the longer t1/2 and exponential dose-response curve difference, but ehh... that's what the site is for lol.

 

[ebola?]

I'm not saying you are way off. I think your model may just need a bit of tuning. Are you familiar with the different adrenergic receptor classes and which areas they're found in the body? Meth and amp stimulate the release of proportionally different NE/E ratios, but the location of those adrenergic receptors varies quite a bit from person to person. The effects of NE overlap with Epi both by location of A1,B1,A2,B2 receptors and by actual physiological response to ligand binding. Amp tolerance varies widely... this is why.

I'm pretty sure that epinephrine is taken up by the NE transporter, so I don't think that it would be possible for this ratio to vary except in terms of overall ratio of central to peripheral effects. This would suggest again that meth is less adrenergic.

the location of those adrenergic receptors varies quite a bit from person to person. The effects of NE overlap with Epi both by location of A1,B1,A2,B2 receptors and by actual physiological response to ligand binding. Amp tolerance varies widely... this is why.

Right, but we're talking about central tendencies of varied substances, not varied responses between individuals.

ebola

 

[Seppi]

As for the research you posted... here is the conclusion summary from "Imaging studies..."

CONCLUSION:
Clarification of the neurological consequences of chronic AMPH treatment for ADHD is needed.

Don't browse a paper and spit it out as evidence unless you're prepared to defend it. Your brain normally upregulates transporter systems being used, which means changes in the mass and density of the brain will naturally take place upon use of psychoactive drugs. The authors noted 'trophic' growth, which indicates the type of growth is not yet understood (as of 2007). By definition, this means it cannot be labelled 'neuroprotective' until further studies are done. Neuroplastic? possibly.

Hate to be a jerk, but your research is weak sauce and shouldn't be cited as evidence of anything other than what is stated in the text.

You responded to 1 of 3 papers that I was quoting, which was also the oldest review of the three. On its own, that paper means jack shit since its just on DAT - the point was to contrast with the abuse toxicity indicated just before it. So you did a good job at ignoring 2/3rds of my argument in your response.

When I said I don't want to rewrite what I already wrote, I was referring to the fact that, over the past several months, I rewrote virtually all of the amphetamine wikipedia article, which is the citation/content you've completely ignored. Hence, I was also referring to a meta-analysis and review of MRI studies which discuss/indicate neurogenesis and neuroprotection.

And while I don't like to cite in vitro or animal studies, here's some statements about neurogenesis and non-neurotoxic doses in rats. CART peptides are also neuroprotective and neurogenerative in vitro. (stated in the drugbank and pubchem amph entries)

All that said, as you probably know, water and salt both have toxidromes, and under certain conditions, can induce central pontine myelinolysis. My point: all substances (ignoring direct neurotoxins) have a neurotoxic threshold dose (i.e., if only being the one that kills you - necrosis + neurons = NTox). That said, it's completely pointless to talk about indirect toxicity while throwing around the word "neurotoxicity". Unless it it's a DIRECT neurotoxic reaction (i.e., .0000001 mg of a drug produces toxicity to neurons), then the discussion is just about toxic overdose, which is when we're back to talking about water intoxication.

 

[ebola?]

That said, it's completely pointless to talk about indirect toxicity while throwing around the word "neurotoxicity". Unless it it's a DIRECT neurotoxic reaction (i.e., .0000001 mg of a drug produces toxicity to neurons), then the discussion is just about toxic overdose, which is when we're back to talking about water intoxication.

Perhaps to repeat, I disagree vehemently. Downstream/indirect mechanisms exerting neurotoxic effects loom large in most examples of neurotoxicity (perhaps all cases if we consider intracellular mechanisms downstream), and they prove particularly relevant if the conditions necessary for the function of those downstream mechanisms are ubiquitously present.

But this doesn't really invalidate your overall points, and I don't want to turn this into a debate over what is indirect vs. direct.

ebola

 

[endotropic]

All that said, as you probably know, water and salt both have toxidromes, and under certain conditions, can induce central pontine myelinolysis. My point: all substances have a neurotoxic threshold dose (i.e., if only being the one that kills you - necrosis + neurons = NTox). That said, it's completely pointless to talk about indirect toxicity while throwing around the word "neurotoxicity". Unless it it's a DIRECT neurotoxic reaction (i.e., .0000001 mg of a drug produces toxicity to neurons), then the discussion is just about toxic overdose, which is when we're back to talking about water intoxication.

I'm having trouble understanding the distinction you're trying to make here.

First of all it doesn't matter whether it takes 1 picogram or 1 kilogram to produce toxicity, all that matters is the toxic dose compared to a typical dose. If that typical dose causes toxicity then that compound is toxic, even if grams and grams were taken.

Concerning the direct vs. indirect toxicity argument, would you say that the effects following MPTP ingestion are "just a toxic overdose"? You would have to ingest several milligrams before the Parkinsonian symptoms occur, and the MPTP needs to be converted to the toxic metabolite MPP+, so that means that MPTP toxicity is equivalent to water intoxication?

 

[Seppi]

This analogy is irrelevant, as people often take large doses of stimulants, but not water or salt.

ebola

...that wasn't an analogy.
I was stating (with 2 examples, not analogs) that they're all indirect neurotoxic effects and hence in the exact same class of toxicity. Arbitrary variances in toxicity incidence don't somehow make that a false statement.

 

[Seppi]

No, MPTP is a known direct toxin - the substance itself is the toxin, so .0000001mg of MPTP produces toxicity to neurons.

Maybe to clarify, amphetamine neurotoxicity is known to result from overwhelming the radical scavenger system in neurons; this requires a sufficiently high dose of amph because the cytosolic concentration of dopamine (released from VMAT2) needs to rise above a certain threshold for ROS/dopa-quinone production production to overwhelm this system. Reference graphic for meth might be helpful

There's always dopamine in the cytosol of a normal dopamine neuron, so there's always some radical activity.

 

[ebola?]

I was stating (with 2 examples, not analogs) that they're all indirect neurotoxic effects and hence in the exact same class of toxicity. Arbitrary variances in toxicity incidence don't somehow make that a false statement.

Quite pedantically, to present to exemplars as bearing shared general characteristic activity is to say that they function analogously. But I agree that my point was poorly worded. However, my contention was that your statement was irrelevant, not false. I mean, if we want to use the category of "toxicity", it's a bit silly to qualify everything as "toxic" or "non-toxic" or think about dosage in all or nothing terms.

all that matters is the toxic dose compared to a typical dose. If that typical dose causes toxicity then that compound is toxic

Indeed, this appears to me to be a sensible way of thinking about this stuff.

ebola

 

[21p]

I'm pretty sure that epinephrine is taken up by the NE transporter, so I don't think that it would be possible for this ratio to vary except in terms of overall ratio of central to peripheral effects. This would suggest again that meth is less adrenergic.

Receptor density varies based on the individual's genetics, environmental conditioning, and health. I know you don't think the 6+ receptor classes are evenly distributed throughout the body. If you've got a copy of McGraw Hill's Pharmacology, check out the section on adrenal receptor location by class.... it gives a very thorough overview of all 20+ effects and where they occur. There's also that damn fine graph comparing the effects of NE/Epi/Dopa.

Side rant: there's a difference between posting for ego vs. public service. I'm guilty of it myself, but when some kid stumbles into a section looking for advice on potentially dangerous decisions, he should be given a direct and simple explanation... "it's so simple for me, i must have a hard time...." no. If you understand the science, you can teach it to a sixth-grader. The truth about amphetamines and friends: we do not truly understand whether amphetamines can be taken therapeutically for a lifetime without damage because we're still on the 'first batch' of adderall babies. I'm not anti-med or adderall, but I do think you will see adderall-stoked heart failure in our years. I know the research says 'no risk', but all of my professors agree we aren't yet able to isolate all the variables required for decent experiments with sympathomimetics, <---big word mothafucka lol...



I would caution anyone who thinks amps are a 'supplement' to really look at what we know about how they work and sleep on it.

 

[Seppi]

Direct toxicity is defined as positive statistical correlation without a threshold effect. (in defining it that way, it captures all compounds that produce strictly monotone toxicity effects and some pathological cases)

The examples were arbitrary because the dose is arbitrary. The point is these drugs don't start producing a toxic effect until some nontrivial dose is reached to begin a neurotoxic cascade.

"Average dose" is both arbitrary and undefined with many neurotoxins (e.g., non-medications).

 

[ebola?]

Receptor density varies based on the individual's genetics, environmental conditioning, and health. I know you don't think the 6+ receptor classes are evenly distributed throughout the body. If you've got a copy of McGraw Hill's Pharmacology, check out the section on adrenal receptor location by class.... it gives a very thorough overview of all 20+ effects and where they occur. There's also that damn fine graph comparing the effects of NE/Epi/Dopa.

Actually, my apologies: I've been missing the forest for the trees this whole time and arguing against minutiae rather than your prior main point, and really wasting everyone's time. :x* So I'm wondering if you know, off hand, which subclasses of adrenergic receptors meth is preferentially selective for in comparison to those amp is selective for (and I'd expect this to vary by stereoisomer too). On the other hand, neither is a strong direct adrenergic agonist, particularly meth, so I wouldn't expect these differences to explain much about how the cardiotoxic effects differ between the two.

I'll try to get ahold of the text to consult and get back to you.

The truth about amphetamines and friends: we do not truly understand whether amphetamines can be taken therapeutically for a lifetime without damage because we're still on the 'first batch' of adderall babies. I'm not anti-med or adderall, but I do think you will see adderall-stoked heart failure in our years. I know the research says 'no risk', but all of my professors agree we aren't yet able to isolate all the variables required for decent experiments with sympathomimetics

I consider this argument sound, particularly if we err on the side of epistemological caution. Sorry if I inspired said rant.

Direct toxicity is defined as positive statistical correlation without a threshold effect. (in defining it that way, it captures all compounds that produce strictly monotone toxicity effects and some pathological cases)

Oooooh. I have been talking about "directness" in a different sense, that of physiological mechanism. Eg, exposure of neural tissue to hydrochloric acid is highly directly neurotoxic due to immediate tissue destruction, whereas various types of excitotoxicity are far more indirect. In this sense, a mere statistical correlation is the utter apex of indirectly measured toxicity, as all mechanisms are black-boxed. But I'm wondering, why should we preclude statistical trends with threshold effects?

ebola
*I blame sleep deprivation, but really, I've embarrassed myself.

 

[Seppi]

@21p: What's the ISBN # of that pharm text?

@ebola: omitting the threshold effect clause would result in a hypothetical completely biologically inactive/safe compound being classed as a direct neurotoxin (or just a "toxin") merely due to the fact that a sufficiently large quantity of any substance will kill a person (via mechanical stress). Even if the dose is stupidly high, since death involves a toxic process (by definition), that would produce a positive (even if extremely small) correlation between dose and toxic reactions in an associated sample dataset.

Toxicity is basically just a catch-all term for overdose that includes non-pharmaceuticals (grass, sand, pesticides), granted, it's a less general concept, since toxicity is a type of OD in indirectly toxic pharmaceuticals. For direct toxins, "toxicity" is a meaningless concept because it's a toxin; i.e., any quantity of the substance produces toxicity, so the "toxicity level/threshold" is just 0 mass.
That's my best guess as to why it's defined that way at least.

It's not a perfect definition, but it prevents safe compounds from being grouped with tetrodotoxin, aflatoxin, ROS, etc, simply based upon the aforementioned correlational technicality.

 

[Immunator]

So basically what you're all saying is that (Meth)amphetamines can be safe for you recreationally in a one time low dose of under 100mg without any redosing no more than once every two weeks?

 

[Seppi]

Meth is a direct neurotoxin to DA neurons, so... there isn't a "safe dose" for preventing that.

I'm not sure it's a good idea to use either meth isomer. Funny that L-meth is OTC in the US.

This is all human neuroimaging:

"Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...
Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ...
There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ...
Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007)."

From
Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213.

 

[Immunator]

That has only to do with addicts. Totally irrelevant.

 

[ebola?]

So basically what you're all saying is that (Meth)amphetamines can be safe for you recreationally in a one time low dose of under 100mg without any redosing no more than once every two weeks?

NO, no. That's a fucking huge dose (assuming 100 percent purity). It's actually unclear what dosage would be low enough as to present negligible neurotoxic danger.

ebola