Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

[Epsilon Alpha]

But that doesn't address the down-regulation supplements cause, and also how the brain quickly and effectively builds a defense against even the most potent neurotoxins, at least at recreational doses, we aren't IV'ing MPTP here, and it does it on it's own.

http://www.ncbi.nlm.nih.gov/pubmed/15959853

Very interesting, any info on the relevant dosage conversion for humans? I've always avoided looking at MAO-B inhibitors because there's the potential for serious adverse reactions. This might also address the issue of continued cell death days or weeks after the last dose in a binge type situation.

As for the melatonin though, I'm tempted to say it might have more to do with it binding to receptors elsewhere in the body at the 25mg/kg doses they gave. I'll have to check out how this weighs in with the larger body of evidence suggesting melatonin exerts a protective role in vivo and in vitro. But still, this is very unexpected to say the least.

http://www.ncbi.nlm.nih.gov/pubmed/20738755
http://www.ncbi.nlm.nih.gov/pubmed/20374443
http://www.ncbi.nlm.nih.gov/pubmed/19386024
http://www.ncbi.nlm.nih.gov/pubmed/19409439

 

[Epsilon Alpha]

How would this apply to methylphenidate's neurotoxicity or tolerance? What doses would causes mild to severe changes by low to high doses of methylphenidate, I would think that they the synapses would be spread further apart and a lot less because of down regulation. Is this down regulation permanent if taken during your childhood and adolescence's developing brain, and if it's not just down regulation that is in effect with methylphenidate, what other things come into play that would create long-term changes?

I recall MPH is generally associated with improved long term measures of focus in humans but increased anxiety and depression if given to children. MPH is a lot more than a DRI, infact it increases DA concentrations in the synapse faster than DAT blockade alone would predict, so its quite a different can of worms.

Also, there is some info suggesting it may promote apoptosis at clinically used levels in rats at least.

 

[chaultistic]

I recall MPH is generally associated with improved long term measures of focus in humans but increased anxiety and depression if given to children. MPH is a lot more than a DRI, infact it increases DA concentrations in the synapse faster than DAT blockade alone would predict, so its quite a different can of worms.

Also, there is some info suggesting it may promote apoptosis at clinically used levels in rats at least.

So does it cause release of dopamine like amphetamine, but differently? You say even at low doses it can causes apoptosis, does MPH only cause this, and does AMPH also cause this? If so, which one would be cause more apoptosis? I feel very slow and dumb now after taking it for so long, and I don't know if I should get Focalin or get on Dexedrine as the Ritalin is not doing anything for me. I was part of the Ritalin generation, and being honest, would you say I don't have much of a brain left after being on them for so long, and in a moderately high dose? Don't have to sugar coat it, I already feel as if my brain is empty and brain damaged beyond repair. Would you think moving up to amphetamines would only speed up the damage already done, or do you think I could find a dose that would be able to be maintained for a long while so I can continue without being useless?

 

[atrollappears]

I recall MPH is generally associated with improved long term measures of focus in humans but increased anxiety and depression if given to children.

Eh there are somewhat conflicting reports. The study you referred to found decreased cocaine self-administration, but another study, giving ritalin in adolescence, found an increase.

Edit:
And chaultistic, I too often wonder about what long-term effects being medicated and doing drugs in adolescence have had on me. But the fact of the matter is that we are who we are now, and nothing will be gained from trying to discern how the past may have affected the present. Treat your brain well and become a person you are happy with---the brain is an amazing thing, and you certainly still have the ability to do so.

 

[ebola?]

Thanks, EA, for consolidating these data! The prior thread was getting slightly unwieldy to read through.

ebola

 

[atrollappears]

Epsilon Alpha, you may find this interesting:

http://onlinelibrary.wiley.com/doi/10.1196/annals.1403.019/full
(if that link doesn't work for you, try this http://onlinelibrary.wiley.com/doi/10.1196/annals.1403.019/abstract)

Edit: Some research suggests that ALC should actually decrease the response to amphetamine (though paradoxically it increases it to cocaine) so I'm going to remove it from my stack tomorrow and see if I notice a difference. Hardly empirical, but oh well.
Update: Skipped my ALC dose today, and I noticed an increase in the effects of the amph, both in terms of behavioral activation and inhibition. So, looks like ALC may block amphetamine, probably from its effects on cell membranes. I still recommend alpha lipoic acid though, if you have some tums xD

Edit 2: To those who use cocaine or MPH, you might find ALC of interest, because as I mentioned ALC increases the response to cocaine, but I neglected to mention the surprising magnitude of the difference: dopamine increase due to cocaine was *doubled* and serotonin increase was also increased by some similarly surprising factor I forget.

 

[Nagelfar]

Edit: Some research suggests that ALC should actually decrease the response to amphetamine (though paradoxically it increases it to cocaine)

Perhaps ALCAR has some role in the increased versus decreased instances of Alzheimer's in chronic amphetamine users as opposed to life long cocaine users.

 

[atrollappears]

Perhaps ALCAR has some role in the increased versus decreased instances of Alzheimer's in chronic amphetamine users as opposed to life long cocaine users.

Yeah, it does increase acetylcholine release, and it shows promise in age-related cognitive impairment (20% increase in working memory when combined with a-lipoic acid). I wonder, though, how the administration of amphetamine/cocaine would affect ALC levels rather than ALC affecting the response to those chemicals...
Maybe people with low endogenous ALC levels prefer amph and those with high prefer cocaine? xD Or more generally (and more probably) the basic metabolic processes, which are affected by ALC and influence cognitive function esp. with respect to aging, affect the response to cocaine and amphetamine in such a way that those more prone to Alzheimer's prefer amphetamine and vice versa.

 

[chaultistic]

Yeah, it does increase acetylcholine release, and it shows promise in age-related cognitive impairment (20% increase in working memory when combined with a-lipoic acid). I wonder, though, how the administration of amphetamine/cocaine would affect ALC levels rather than ALC affecting the response to those chemicals...
Maybe people with low endogenous ALC levels prefer amph and those with high prefer cocaine? xD Or more generally (and more probably) the basic metabolic processes, which are affected by ALC and influence cognitive function esp. with respect to aging, affect the response to cocaine and amphetamine in such a way that those more prone to Alzheimer's prefer amphetamine and vice versa.

Again, although methylphenidate is similar to both amphetamine and cocaine, does this mean that people who respond well to methylphenidate instead of amphetamine have high ALC levels, (since it works as a DNRI, and cocaine is a DNSRI) and would cocaine or methylphenidate predispose someone to Alzheimerz as well?? What would methylphenidate replicate more between cocaine and amphetamine? I think this thread should include all RX'D amphetamine-like substances (and cocaine) , unless the reason you haven't is because that they're too different, but they generally do a few of the same things.

 

[atrollappears]

Again, although methylphenidate is similar to both amphetamine and cocaine, does this mean that people who respond well to methylphenidate instead of amphetamine have high ALC levels, (since it works as a DNRI, and cocaine is a DNSRI) and would cocaine or methylphenidate predispose someone to Alzheimerz as well?? What would methylphenidate replicate more between cocaine and amphetamine? I think this thread should include all RX'D amphetamine-like substances (and cocaine) , unless the reason you haven't is because that they're too different, but they generally do a few of the same things.

My comment about ALC levels was mostly meant to be a joke, because of how common it is that people say X condition is due to deficiency of Y-ine, and how rare it is that it's anywhere close to that simple. If I understood Nagelfar correctly, he was saying that cocaine (so *possibly* methylphenidate by extension, because methylphenidate and cocaine work similarly) users have a lower risk of Alzheimer's. Note that this does not mean cocaine decreases the risk of Alzheimer's, because as I theorized, it's possible that cocaine users simply have some trait that would make them less vulnerable to Alzheimer's whether or not they did cocaine. Amphetamine and methylphenidate/cocaine actually work very differently, since amphetamine actually releases the neurotransmitter while MPH or cocaine only stop it from being stored (so obviously the answer to your question is that MPH is more like cocaine). As far as we have observed, methylphenidate and cocaine do not have neurotoxic effects, so there's really no reason to discuss their neurotoxicity. They may have adverse effects, some of which may be neurological, but that's not necessarily neurotoxicity, which includes actual damage to the neurons.

Also, more personally, I read your thread, and you're not going to get anywhere by worrying about what may have affected you in the past. Maybe MPH or seroquel or what-have-you affected your brain permanently to some significant degree (and it's entirely possible that they didn't). But, the human brain is very resilient (more resilient than rats' brains, from what I can tell). Even if you think that you've been impaired to some degree, you should remember that your brain is constantly working to repair and recover, so you should treat it well and start working toward the person you want to be, rather than dwelling on the past. I'd bet that things will get a lot better than you think they will.

 

[atrollappears]

Eplison Alpha and atrollappears, what do you two think of of the possibility of an anti-oxidant stack turning pro-oxidant in presence of MDMA/METH? Also, are you aware daily anti-oxidants will likely DOWNREGULATE endogenous production of the brain's own anti-oxidants? This means if one day you skip those anti-oxidants and something in your brain causes damage that requires internal protection, we're fucked. Selegiline I believe up-regulates said production, one reason why it's so interesting.

Alpha lipoic acid is now believed to exert most of its antioxidant effects by activating the body's own antioxidant defense mechanisms, so that might avoid that issue of down-regulation. It doesn't seem to form large amounts of pro-oxidative metabolites, but supposedly it activates the body's antioxidative mechanisms through somehow being pro-oxidative (though I can't seem to get access to the article which supposedly says this), but if that's true, then even if it did go pro-oxidative then it wouldn't be a problem. There aren't any studies on ALA and amphetamine, but it does completely block long-term serotonin depletion due to MDMA.

Edit: On a side note, you have to munch a lot of antacids to take ALA with amphetamine (acidity inhibits absorption and such). Stuff's pretty damn hard on the stomach.

 

[Nagelfar]

...your brain is constantly working to repair and recover, so you should treat it well and start working toward the person you want to be, rather than dwelling on the past. I'd bet that things will get a lot better than you think they will.

Good advice atrollappears.

chaultistic, MPH, to my knowledge & like cocaine, shows neuroprotective traits & possibly mechanisms. Though it causes acute anhedonia after long bouts of use, recovery (years of abstinence) *may* put you in a better situation than you were before using for all that is known. Amphetamines however, seem to indicate the opposite and put one in a more thorough-goingly compromised condition and be less well neurologically tolerated after chronic use.

 

[atrollappears]

Amphetamines however, seem to indicate the opposite and put one in a more thorough-goingly compromised condition and be less well neurologically tolerated after chronic use.

Hahah, but don't we love 'em anyway...
And that's after chronic use, unless you use it in adolescence, in which case you were resistant to neurotoxic damage then (though not cortical impairment) and will continue to be resistant to it into adulthood, if rats are any indication. xD But in what sense do you mean a chronic user is more vulnerable? More vulnerable to psychosis, certainly, but I think tolerance/sensitization/whatever-the-hell-actually-happens-in-humans is protective against neurotoxicity, correct?

 

[Nagelfar]

I think tolerance/sensitization/whatever-the-hell-actually-happens-in-humans is protective against neurotoxicity, correct?

Sensitization, I believe, is an exacerbation of neurotoxicity (in its own case) as per definition. At least if I recall correctly studies show as much.

 

[atrollappears]

Sensitization, I believe, is an exacerbation of neurotoxicity (in its own case) as per definition. At least if I recall correctly studies show as much.

At least as far as dopaminergic neurotoxicity goes, it looks like tolerance develops rather than sensitization. http://www.sciencedirect.com/science/article/pii/S0006899397005428

 

[Epsilon Alpha]

http://www.sciencedirect.com/science/article/pii/S0014299998008516 THC increases sensitization.
http://www.sciencedirect.com/science/article/pii/S0165017399000491 Evidence supporting a developmental theory of schizophrenia, and gating issues in the limbic system.
http://www.sciencedirect.com/science/article/pii/S003193840800379X Sensitization to amphetamines appears to require a certain biological basis, and rats resistant to sensitization actually show reduced movement relative to sensitized rats. Also, interestingly enough apparently ~40% of SD rats do not sensitize. High corticosterone and low 5HT in the mPFC appear to be involved in sensitization

http://www.springerlink.com/content/y13g4j7287330848/ And some sweet reading on mGlu5 vs DA mediated reward

 

[Epsilon Alpha]

Epsilon Alpha, you may find this interesting:

http://onlinelibrary.wiley.com/doi/10.1196/annals.1403.019/full
(if that link doesn't work for you, try this http://onlinelibrary.wiley.com/doi/10.1196/annals.1403.019/abstract)

Edit: Some research suggests that ALC should actually decrease the response to amphetamine (though paradoxically it increases it to cocaine) so I'm going to remove it from my stack tomorrow and see if I notice a difference. Hardly empirical, but oh well.
Update: Skipped my ALC dose today, and I noticed an increase in the effects of the amph, both in terms of behavioral activation and inhibition. So, looks like ALC may block amphetamine, probably from its effects on cell membranes. I still recommend alpha lipoic acid though, if you have some tums xD

Edit 2: To those who use cocaine or MPH, you might find ALC of interest, because as I mentioned ALC increases the response to cocaine, but I neglected to mention the surprising magnitude of the difference: dopamine increase due to cocaine was *doubled* and serotonin increase was also increased by some similarly surprising factor I forget.

I find this very interesting, would you mind going into a bit more detail for those who simply browse this thread? I'm mulling over some reading trying to figure out whats going on on during my breaks for my term paper. You know you're a future Ph.D when your breaks are going from one pubmed topic to another...

 

[Epsilon Alpha]

Arguments for various antioxidants

CoQ10 related compounds​

The antioxidant nature of CoQ10 derives from its energy carrier function. As an energy carrier, the CoQ10 molecule is continually going through an oxidation-reduction cycle. As it accepts electrons, it becomes reduced. As it gives up electrons, it becomes oxidized. In its reduced form, the CoQ10 molecule holds electrons rather loosely, so this CoQ molecule will quite easily give up one or both electrons and, thus, act as an antioxidant.[9] CoQ10 inhibits lipid peroxidation by preventing the production of lipid peroxyl radicals (LOO). Moreover, CoQH2 reduces the initial perferryl radical and singlet oxygen, with concomitant formation of ubisemiquinone and H2O2. This quenching of the initiating perferryl radicals, which prevent propagation of lipid peroxidation, protects not only lipids, but also proteins from oxidation. In addition, the reduced form of CoQ effectively regenerates vitamin E from the a-tocopheroxyl radical, thereby interfering with the propagation step. Furthermore, during oxidative stress, interaction of H2O2 with metal ions bound to DNA generates hydroxyl radicals and CoQ efficiently prevents the oxidation of bases, in particular, in mitochondrial DNA.[9] In contrast to other antioxidants, this compound inhibits both the initiation and the propagation of lipid and protein oxidation. It also regenerates other antioxidants such as vitamin E. The circulating CoQ10 in LDL prevents oxidation of LDL, which may provide benefit in cardiovascular diseases.

Pros: half life longer than that of amphetamine, known to cross the BBB, well studied at doses up to several grams a day, known side effect profile, reduction in expression of pro-inflammatory genes, documented reductions in systolic blood pressure, and has been shown in vivo to prevent the progress of Parkinson's disease.
Cons: Unknown if constant dosage will cause downregulation of endogenous antioxidant mechanisms, GI disturbances possible, possible absorption issues.
http://en.wikipedia.org/wiki/Ubiquinol
http://en.wikipedia.org/wiki/Coenzyme_Q10

alpha lipoic acid ​

Pros: iron chelator (would help prevent DA auto-oxidation), improvements in cardiovascular disease, upregulation of body's antioxidant defense mechanisms, possible protection against stim dick (no joke), easily, crosses BBB, and reduction of inflammation.
Cons: high doses may prevent benefits of CR diet on longevity, very short half life.
http://en.wikipedia.org/wiki/Lipoic_acid
http://msj.sagepub.com/content/16/4/387.full.pdf+html

Up next: PQQ

 

[Amu]

Epsilon Alpha, any similar info on ALCAR/NAC/Selenium/Melatonin? Especially whether they up-regulate or down-regulation endogenous mechanisms?

 

[atrollappears]

I find this very interesting, would you mind going into a bit more detail for those who simply browse this thread? I'm mulling over some reading trying to figure out whats going on on during my breaks for my term paper. You know you're a future Ph.D when your breaks are going from one pubmed topic to another...

Going into detail about what exactly? The studies I read indicated that the researchers seemed to believe that ALC was inhibiting the action of amphetamines via its actions on cell membranes. As far as its diminishing effect on the amphetamine experience, I can elaborate on that as needed (it especially diminishes 4-FA I've found, such that while I am not on ALC I find 4-FA extremely enjoyable, and while I am on ALC I find 4-FA not worth taking).

alpha lipoic acid ​

Pros: iron chelator (would help prevent DA auto-oxidation), improvements in cardiovascular disease, upregulation of body's antioxidant defense mechanisms, possible protection against stim dick (no joke), easily, crosses BBB, and reduction of inflammation.
Cons: high doses may prevent benefits of CR diet on longevity, very short half life.
http://en.wikipedia.org/wiki/Lipoic_acid
http://msj.sagepub.com/content/16/4/387.full.pdf+html

Up next: PQQ

I believe that ALA's plasma concentration is not necessarily correlated with respect to time with its effectiveness. I've heard that the upregulation of endogenous antioxidant mechanisms lasts longer than ALA itself in the body, though I can't find evidence for that. Also, what's "CR diet"?