Meth neurotoxicity avoidable with infrequant use?

[Crankinit]

I'm curious how much the neurotoxic effect of meth is related to frequantly of use? I haven't used any in a good 6 months or so but would like to get back into it again a little, but I'm worried about doing any (further?) damage to my brain (even though I was never a daily user. I did go on a fair few thurs - monday type binges and often combined it with MDMA, which I'm told compounds the damage)

Basically I'm paranoid as fuck about my mental health these days, I'd hate to go into any kind of cognitive decline because well, you only have one brain, I don't want to fuck it up. I have a very materialistic world view, as far as I'm concerned my brain is 'me'.

My question is, if somebody were to use meth irregularly and responsibly (if you can call any meth use responsible), would they be able to completely avoid any dopaminergic or serotonergic damage? Is the neurotoxicity something that only presents with regular use, or is it something that will happen every single time you use, and just accumulates in correlation to how often you use?

Is it X amount of meth = X amount of damage, or is the damage something that only occurs when the brain is under the strain of heavy binging and regular daily useage? And if the latter, where is this threshhold?


For the purpose of this discussion, I'm talking maybe once every 3 - 6 weeks, no more than 1/4 or 1/2 gram, and staying awake absolutely no more than two days*. Also on a regime of supplements including fish oil, l-tyrosine (following comedowns), magnesium, anti-oxidants and, if I can get it, piracetam. No more poly-drug use either.


*I'm well aware of how addictive meth is and how hard it will be to hold myself to those restrictions.

I wasn't sure if this really belonged in ADD, but I figured it might be a little beyond the scope of BDD. Really appreciate any input on the topic guys

 

[permastoned]

If you are worried about damage, then take the necessary precautions. Eat 20 grams of vitamin C next time you use throughout the night, popping them and sucking on them. Then have a reasonable amount of vitamin E too. They will work well to reduce oxidative stress (and damage) in le brain. The other thing is try and stay cool.

Even better is selegiline because it enhances the effect of the amphetamine too! And BLOCKS neurotoxicity. Hard to get, though, especially in Aus because the condition for prescribing is

Restricted benefit
Late stage Parkinson's disease as adjunctive therapy in patients being treated with levodopa—decarboxylase inhibitor combinations.

You can still get it prescribed without that, it just means that you pay full price, which isn't that much anyway. But the doc would be doing it 'off-label' and some docs don't like doing that.

http://www3.interscience.wiley.com/journal/77002326/abstract?CRETRY=1&SRETRY=0

Abstract
MDMA-induced 5-HT neurotoxicity has been proposed to involve oxidative stress due to increased formation of hydroxyl radicals. Recently, MDMA-induced 5-HT neurotoxicity has been shown to be accompanied by a suppression of behavioral and neurochemical responses to a subsequent injection of MDMA. The intent of the present study was to examine whether suppression of the MDMA-induced formation of hydroxyl radicals by an antioxidant, ascorbic acid, attenuates both the MDMA-induced depletion of 5-HT and the functional consequences associated with this depletion. Treatment of rats with ascorbic acid suppressed the generation of hydroxyl radicals, as evidenced by the production of 2,3-dihydroxybenzoic acid from salicylic acid, in the striatum during the administration of a neurotoxic regimen of MDMA. Ascorbic acid also attenuated the MDMA-induced depletion of striatal 5-HT content. In rats treated with a neurotoxic regimen of MDMA, the ability of a subsequent injection of MDMA to increase the extracellular concentration of 5-HT in the striatum, elicit the 5-HT behavioral syndrome, and produce hyperthermia was markedly reduced compared to the responses in control rats. The concomitant administration of ascorbic acid with the neurotoxic regimen of MDMA prevented the diminished neurochemical and behavioral responses to a subsequent injection of MDMA. Finally, a neurotoxic regimen of MDMA produced significant reductions in the concentrations of vitamin E and ascorbic acid in the striatum and hippocampus. Thus, the MDMA-induced depletion of brain 5-HT and the functional consequences thereof appear to involve the induction of oxidative stress resulting from an increased generation of free radicals and diminished antioxidant capacity of the brain. Synapse 40:55-64, 2001. © 2001 Wiley-Liss, Inc.

 

[theWorldWithin]

I believe methamphetamine causes damage at all dosages, unlike plain amphetamine which only exhibits neurotoxicity past a particular threshold dosage. But to answer your question more specifically, the damage is likely increase orders of magnitude depending on the dosage and conditions. And to be honest, 250-500 mgs of meth is a hell of a lot of speed, far beyond the threshold dose for regular amphetamine, so you put 2 and 2 together on that one. It is my understanding that all heavily serotongenic amphetamines are neurotoxic at all dosages, it is just a question of degree.

 

[Sturnam]

Well, firstly I think you're confusing neurotoxicity with behavioral or mental changes. Meth will be neurotoxic at any recreational dose, but that doesn't necessarily mean it will impair your cognitive function.

For example, Parkinson's symptoms only really start showing up when there is a substantial (50-80%) loss of dopaminergic neurons.

Of course, some areas have less neurons than others and can accumulate appreciable damage much more quickly.

If you're really worried, then just take some of the more powerful anti-oxidants, like R-ALA or Acetyl-L-carnitine. Both of those have shown lots of promise as far as MDMA induced neurotoxicity.

And lastly, I stress that keeping cold/cooler is important, or at least not getting really hot. There are countless studies that show that neurotoxicity is dose and temperature dependent. Basically, the higher the temperature, the more damage.

But I don't think anyone will be able to tell you when cognitive damage will show up. Everyone is different. Just listen to you body/brain, and give it plenty of rest inbetween doses to asses the damage.

 

[Crankinit]

Well, firstly I think you're confusing neurotoxicity with behavioral or mental changes. Meth will be neurotoxic at any recreational dose, but that doesn't necessarily mean it will impair your cognitive function.

How does that work exactly? Aren't the behavorial and mental changes caused by the neurotoxicity?

The body temperature is an issue, since I'd be using it while partying, so we're talking nights of dancing, hot crowded clubs, the usual. But no more so than MDMA I guess.

Basically what I'm worried about is long term effects that won't reverse themselves after complete abstinance. I know that with any stimulant you're going to see short term changes when the drug wears off and probably take a couple days or weeks to get back to your normal self. I can deal with that, but I value my intellect and I'm very paranoid about doing any (further?) damage to it.

Even better is selegiline because it enhances the effect of the amphetamine too! And BLOCKS neurotoxicity. Hard to get, though, especially in Aus because the condition for prescribing is

That sounds pretty interesting. I'll look into it, but I'm not sure what my chances of getting any are.

Exactly how effective are anti-oxidants and vitamin C/E when it comes to protecting from damage?

 

[Sturnam]

How does that work exactly? Aren't the behavorial and mental changes caused by the neurotoxicity?

They're caused by neurotoxicity, but neurotoxicity does not equal cognitive changes. Take for example the Parkinson's thing. It takes 50-80% of the neurons in the area to die before any symptoms show up.

So, say for example you have 1000 neurons. You could have meth induced neurotoxicity that kills say 100 neurons, but the other 900 are able to compensate well enough that there are no noticable cognitive defects.

Exactly how effective are anti-oxidants and vitamin C/E when it comes to protecting from damage?

I don't think vitamin C/E are that great, especially with greater than normal stresses. I suggested R-Alpha Lipoic Acid or Acetyl-L carnitine, which have both proved pretty good for preventing MDMA neurotoxicity, so I'm guessing they wouldn't be too bad for meth either.

 

[Crankinit]

But I'd rather not kill 'any' neurons I'm not so much worried about something massive like getting parkinsons, just the small cognitive deficits. Issues with problem solving, short term memory, verbal recall, that kind of thing.

It sounds like I need to just stick to the drugs that don't have any significant neurotoxic effect. Sigh. Somehow I get the feeling that there's nothing else out there that will scratch that itch quite like a nice big toke of meth, but I'm through with gambling with my brain chemistry. I value my intellect far too much to want to take any more risks with it, especially when I feel I've already impacted it to some degree with my previous meth/MDMA use.

 

[nuke]

My thoughts are that idebenone may be the best antioxidant to prevent the toxicity of amphetamines due to its long half life, but I don't think it's been studied for this effect.

 

[Crankinit]

Ok just to follow this along another line of thought, what is it about meth that makes it so damaging to the brain in comparison to something like cocaine? Are there any resources online that explain exactly why it's so damaging?

 

[Sturnam]

As far as damage, I'm just going to compare to amphetamine, since it's really closely related, but vastly different in neurotoxicity terms.

Methamphetamine releases far more serotonin than amphetamine does, and is a slightly stronger dopamine releaser. It is because it releases more serotonin that it is more neurotoxic.

I'm slightly fuzzy on the exact mechanism, but I think it's basically that the neurotransmitters get re-uptaked into the wrong area (serotonin molecules are taken back into dopamine releasing neurons). Then, these "foreign" neurotransmitters are toxic to the neuron. This was also the proposed mechanism for MDMA neurotoxicity for a while, although it's mostly been replaced by the free-radical/oxidative stress theory.

This only happens when they are both released in large amounts at the same time. So back to the amphetamine example, amphetamine releases lots of dopamine, but much less serotonin, so the neurotoxicity isn't nearly as great.

 

[any major dude]

The only long term effects on the brain i've read about that stem from cocaine usage are due to decreased blood flow, which probably has to do with its vasoconstrictive properties, but i'm not sure.

Meth on the other hand can do long term & permenant damage to both seratogenic and dopaminergic pathways, particularly in the limbic system. This can cause permenant deficiencies in the user's ability to experience pleasure, among other things, and happen with a large enough single dose or repeated exposure.

 

[immad]

Ok just to follow this along another line of thought, what is it about meth that makes it so damaging to the brain in comparison to something like cocaine? Are there any resources online that explain exactly why it's so damaging?

I don't know the exact mechanism, but remember that meth has a very long half life. With coke, it's possible to extend the high to your liking and let it end pretty abrubtly when needed. Afaik with meth, you're tied to it for quite some time (never had any, just a few low dosages of regular amph a few years ago). So the area under the plasma concentration curve is usually bigger with meth than with coke I guess.

 

[Crankinit]

The only long term effects on the brain i've read about that stem from cocaine usage are due to decreased blood flow, which probably has to do with its vasoconstrictive properties, but i'm not sure.

Meth on the other hand can do long term & permenant damage to both seratogenic and dopaminergic pathways, particularly in the limbic system. This can cause permenant deficiencies in the user's ability to experience pleasure, among other things, and happen with a large enough single dose or repeated exposure.

Yeah I'm just curious about why coke seems to be relatively safe (heart problems aside) yet meth so damaging. Sturnam's explanation makes sense I guess.

Looks like it's no meth for me. I'd 'really' like to get stuck into it again occasionally, but I'm just not willing to risk any more damage. I'm scared shitless of ending up another brainfried burnout. I've seen where that path takes people and I don't wanna go there.

Also how do you guys feel about the use of the -racetam nootropics as far as recovering from post abuse damage goes? I've heard good things about it with MDMA, but nothing as far as meth goes. Is there anything to that, or is it just a placebo/just the nootropic effect counteracting any cognitive disfunction from the drug abuse?

 

[any major dude]

All stimulants have somewhat similar methods of action, usually mostly through dopaminergic circuitry. Meth also has a seratogenic component, which may have something to do with its toxicity. However, I'd put my money on its potency and long half life.

For example, say you snort 200mg (1/5g) of cocaine. Thats a reasonably large line, and (assuming decent purity) you'll be pretty high for 20-45min, with some residual stimulant activity. Now say you snort 200mg of methamphetamine. Again assuming reasonable purity, you will likely still be high in 12hrs. Given that cocaine tolerance rises rather quickly, most people stop redosing (for the night at least) after a few hours. One dose of meth on the other hand is overstimulating dopaminergic ciruits in your brain for roughly more than twice as long as most people are willing to do cocaine, and more than 12 times the duration of a single dose.

I could be wrong about this, but I think that cocaine's toxic effects are related to inhibition of norepinephrine reuptake, which may account for its higher LD50, as Methamphetamine's lethality is almost certainly related to dopamine & also probably seratonin.

 

[immad]

^Uhm, relativily seen is cocaine far more selective for dopamine than meth. It's meth that relies heavily on NE, not cocaine.

DA R, DA U, NE R, NE U, 5-HT R, 5-HT U

Cocaine: >10000, 478, >10000, 779, >10000, 304
d-Meth: 24.5, 114, 12.3, 48, 736, 2137

For comparison:

d-Amph: 24.8, 34, 7.07, 38.9, 1765, 3830

And give me some of this:

RTI-229: >10000, 0.35, >10000, 19.5, >10000, 362

 

[any major dude]

how old is that chart? Most of the stuff I've read on this is from the 2002-2005 time period. I've read several studies that specifically state cocaine's toxicity is related to epinephrine and norepinephrine, and the subsequent cardiovascular effects.

I've never even seen NE mentioned in an abstract regarding methamphetamine & brain damage.

Here's the abstract from my favorite meth study. You can also read a summary on the nytimes website. Dr. Paul Thompson

and here's a more recent one on cocaine & NE Cocaine effects on Norepinephrine in the Amygdala

 

[Sturnam]

I'm pretty sure cocaine's toxicity (we're talking cardiotoxicity here) is due to the fact that it acts as a local anesthetic. Cocaine analogues that lack this characteristic are pretty non-toxic. That one website about Cocaine & NE in the amygdala seems to say that it doesn't damage the norepinephrine neurons, but simply alters their structure.

All stimulants have somewhat similar methods of action, usually mostly through dopaminergic circuitry. Meth also has a seratogenic component, which may have something to do with its toxicity. However, I'd put my money on its potency and long half life.

Pay up? Because i'm 99% sure that the toxicity is due mainly to the substantial release of dopamine + serotonin. Long half life and potency certainly don't help, as not eating, sleeping, and using absurd amounts per session (quarter of a gram and up) make this worse. But as for the mechanism of neurotoxicity, it is the dual release of neurotransmitters. For example, amphetamine, even when used in binge patterns similar to methamphetamine, doesn't have nearly the same neurotoxicity. Why? Releases a lot less serotonin.

 

[immad]

^D-Meth releases like 2,4 times more serotonin than d-amph and prevents the reuptake 1,8 times better. Does this mean meth is on average ~4,3 times ( 2,4 * 1,8 ) as toxic as d-amph?

 

[nuke]

No, the toxicity is probably many more times greater with meth than that.

The problem is the oxidative metabolism of dopamine via MAO-B as well as the thermogenesis from the large amount of serotonin released in the hypothalamus. When coupled together they seem to cause all sorts of mitochondrial dysfunction and irreversible damage. Glutathione metabolites which are also extremely neurotoxic have the tendency to be produced under these conditions as well.

 

[immad]

Slightly offtopic, but wouldn't MDMA be much more neurotoxic than meth, as the serotonin release is higher?