Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

[atrollappears]

A note about curcumin which is a little concerning: It seems to activate enzymes involved in glutathione-mediated antioxidation. This is potentially counterproductive, as the agent currently thought to mediate MDMA-induced neurotoxicity is an oxidant MDMA metabolite bound to glutathione. If a similar mechanism is at work with (meth)amphetamine, to increase the activity of those enzymes could increase neurotoxicity.

 

[Epsilon Alpha]

A note about curcumin which is a little concerning: It seems to activate enzymes involved in glutathione-mediated antioxidation. This is potentially counterproductive, as the agent currently thought to mediate MDMA-induced neurotoxicity is an oxidant MDMA metabolite bound to glutathione. If a similar mechanism is at work with (meth)amphetamine, to increase the activity of those enzymes could increase neurotoxicity.

Mind posting the study in question? I'm interested to see what enzymes are involved and what the extent of the effects are, curcumin in reasonable doses is in itself a potent antioxidant so depending on the situation may prevent some of the potential oxidative stress.

Also, I'll post more antioxidant info when I get some free time. Been crazy busy lately.

 

[atrollappears]

Mind posting the study in question? I'm interested to see what enzymes are involved and what the extent of the effects are, curcumin in reasonable doses is in itself a potent antioxidant so depending on the situation may prevent some of the potential oxidative stress.

Also, I'll post more antioxidant info when I get some free time. Been crazy busy lately.

http://www.sciencedirect.com/science/article/pii/S1357272598000156
http://online.liebertpub.com/doi/abs/10.1089/ars.2005.7.32

I think that metabolite model of MDMA neurotoxicity theorizes that oxidative stress causes the damage indirectly by inducing glutathione activity. Certainly, something more than oxidative stress is needed to explain what's going on, since alpha-methyldopamine, itself an oxidant, can be injected directly into a rat brain in concentrations sufficient to release and deplete 75% of dopamine, but not cause any long-term depletion.
Still, it's entirely possible that glutathione or metabolites have nothing to do with DAergic toxicity.

Edit: Except apparently glutathione is still protective against MDMA neurotoxicity? http://www.sciencedirect.com/science/article/pii/S0028390802004112
I'm confused.

 

[Epsilon Alpha]

http://www.sciencedirect.com/science/article/pii/S1357272598000156
http://online.liebertpub.com/doi/abs/10.1089/ars.2005.7.32

I think that metabolite model of MDMA neurotoxicity theorizes that oxidative stress causes the damage indirectly by inducing glutathione activity. Certainly, something more than oxidative stress is needed to explain what's going on, since alpha-methyldopamine, itself an oxidant, can be injected directly into a rat brain in concentrations sufficient to release and deplete 75% of dopamine, but not cause any long-term depletion.
Still, it's entirely possible that glutathione or metabolites have nothing to do with DAergic toxicity.

Edit: Except apparently glutathione is still protective against MDMA neurotoxicity? http://www.sciencedirect.com/science/article/pii/S0028390802004112
I'm confused.

Well I did some reading and here's my take on this issue:
-Oxidative stress is one of or the primary mediators of cell damage in MDMA and (Meth)AMP
-Glutathione conjugation up to a point where the body can not remove the resulting conjugates from circulation is good, as it reduces oxidative stress.
-Excess glutatione conjugates act in a unique fashion to cause apoptosis, perhaps recognition by death receptors/ increased uptake/ novel binding affinities?
-While your study is on epithelial cells in the lung, there is the distinct possibility that this may happen in vivo but there is no way in hell I'm paying $59.00 to check the concentrations they used in that study.
-The rat liver study showed only a 1.4x increase in GST, granted its a very small measure of a complex system. My thoughts are that there is only mild effects at relevant human dosage.

But keep up the good work man, ain't no review but peer review =)

But as for a brief summery of what I saw for the antioxidant stuff:
-NAC is really bad long term
-PQQ is too novel to really give a solid review, but has the potential to be stunning so far.
-Selenium is actually required for proper antioxidant defenses, but for the love of god don't megadose it.
-Melatonin is safe up to a gram a day from a few studies I found, no real info on it downregulating anything at reasonable doses.

 

[Amu]

NAC is really bad long-term!? That comes as a shock, why is that so?

 

[atrollappears]

Well I did some reading and here's my take on this issue:
-Oxidative stress is one of or the primary mediators of cell damage in MDMA and (Meth)AMP
-Glutathione conjugation up to a point where the body can not remove the resulting conjugates from circulation is good, as it reduces oxidative stress.
-Excess glutatione conjugates act in a unique fashion to cause apoptosis, perhaps recognition by death receptors/ increased uptake/ novel binding affinities?
-While your study is on epithelial cells in the lung, there is the distinct possibility that this may happen in vivo but there is no way in hell I'm paying $59.00 to check the concentrations they used in that study.
-The rat liver study showed only a 1.4x increase in GST, granted its a very small measure of a complex system. My thoughts are that there is only mild effects at relevant human dosage.

But keep up the good work man, ain't no review but peer review =)

Thanks!
Yeah, ultimately I guess it's not a huge concern, it looks like enhancing glutathione-related processes is actually protective.

Those glutathionyl-alpha-methyldopamine compounds are confusing though. For example, they manage to mimic MDA pharmacologically, even though they have the entire glutathione peptide attached to them. No way that fits through the transporter. So obviously they are being changed into one or more compounds that aren't just alpha-methyldopamine (no SERT affinity, no neurotoxicity injected intracranially), which then account for the neurotransmitter release and probably toxicity.
It seems that this neurotoxicity pathway actually requires the pharmacological action of amphetamines to occur. After all, amphetamines are preferentially toxic to the neurotransmitter system they have a higher affinity for, and AFAIK none are at all toxic to a system they don't activate. Considering the emergent 5-HT toxicity with MDAI + amph, maybe the release leaves neurons vulnerable to toxic metabolites. And since meth causes neurotoxicity even when DA is depleted, it's probably something in the pathway of transporter phosphorylation which causes that, although here I'm assuming DA and 5-HT toxicity are the same.
So we have glutathione, oxidation, glutamate, and microglia. They're very related, and they seem to rely on the direct neurochemical effects of stimulants. Epsilon Alpha (or anyone else), do you have any guesses as to how stimulants might make cells more vulnerable? Or an alternative explanation?

 

[Epsilon Alpha]

NAC is really bad long-term!? That comes as a shock, why is that so?

Well a large part of it is unrelated to its antioxidant action and is more a toxic metabolite issue. NAC is also ridiculous at sequestering NO which may cause future vascular issues at very high doses. So the take home message is don't eat spoonfuls of this stuff, and probably take occasional breaks from it as well.
http://en.wikipedia.org/wiki/Acetylcysteine#Adverse_effects

But, with antioxidants in general, its also an issue of the dose makes the poison. I can find tons of studies showing that reasonable (low) dosing patterns are protective, but also studies showing that higher doses prevent needed upregulation of antioxidant defense mechanisms.
http://www.sciencedirect.com/science/article/pii/S0167488900000367

 

[Epsilon Alpha]

http://www.mindandmuscle.net/forum/41838-amphetamine-sensitization-possible-implications-humans
Hey, started a bit of a side discussion on the sensitization bit over at M&M last week if you want to keep up with what I'm researching. But, this stuff has a lot to do with opioids as well...a

And Redman if you're reading this: Hello my friend!
And J. Foley if you're reading this: get off the drugs man holy fucking Christ.

 

[atrollappears]

Decreased dopamine, tyrosine hydroxylase, and DAT, but normal VMAT (!) and DOPA decarboxylase levels in human methamphetamine users.
http://www.nature.com/nm/journal/v2/n6/abs/nm0696-699.html

VMAT is decreased by meth administration in mouse/rat/primate. This is definitely a major difference that calls into question the validity of extrapolating from these models...

Epsilon Alpha, you mentioned in that thread that immune response is related to amph's effects on the brain. Isn't that a given, though, with amph's microglia activation?

 

[Nagelfar]

Decreased dopamine, tyrosine hydroxylase, and DAT, but normal VMAT (!) and DOPA decarboxylase levels in human methamphetamine users.

I wonder what the decrease in DAT is for DRA (meth) users versus DRI (cocaine) users.

 

[Epsilon Alpha]

Decreased dopamine, tyrosine hydroxylase, and DAT, but normal VMAT (!) and DOPA decarboxylase levels in human methamphetamine users.
http://www.nature.com/nm/journal/v2/n6/abs/nm0696-699.html

VMAT is decreased by meth administration in mouse/rat/primate. This is definitely a major difference that calls into question the validity of extrapolating from these models...

Epsilon Alpha, you mentioned in that thread that immune response is related to amph's effects on the brain. Isn't that a given, though, with amph's microglia activation?

...the hell?
http://www.springerlink.com/content/p6753g35n6521230/
http://www.ncbi.nlm.nih.gov/pubmed/18815269
http://www.jneurosci.org/content/22/20/8951.abstract
http://neuro.cjb.net/content/28/39/9850.short

Looks like VMAT2 is initially downregulated (bad) then upregulated (good) in humans. But this study (comparing VMAT2 in amphetamine vs cocaine in rats) suggests that the localization of vesicles may change with acute or subacute usage. http://www.sciencedirect.com/science/article/pii/S0014299902019854
Well we'll get a better idea when this study comes out http://search.engrant.com/project/y...of_brain_vmat2_in_human_methamphetamine_users

I could be wrong here, but maybe VMAT2 is only implicated in toxicity because of a secondary effect on vesicle transport within the cell. That would explain some of the weirder results, but I'm not 100% on it. Methamphetamine appears to keep vesicles away from the synapse, while cocaine appears to lead to more vesicles being close to the synapse. Not sure if MPH could have the same effect as cocaine, but if so it might be a good idea to cycle AMP and MPH at least on paper...

However there are also a giant stew of other proteins and signals involved in long term amphetamine use. One thing I'm still trying to figure out is how amphetamine but not MCAT activates glial cells, hopefully someone with more expertise in the field of immunology can help me out here.

 

[atrollappears]

However there are also a giant stew of other proteins and signals involved in long term amphetamine use. One thing I'm still trying to figure out is how amphetamine but not MCAT activates glial cells, hopefully someone with more expertise in the field of immunology can help me out here.

Activation of glial cells is a specific marker for neurotoxicity, right? If so, then I'd look toward the metabolites. There's a very specific SAR for what does and does not cause neurotoxicity: amphetamines (not cathinones), but only amphetamines which can be para-hydroxylated (if I may extrapolate from 4-FA and conflate 5-HT and DA toxicity).

I could be wrong here, but maybe VMAT2 is only implicated in toxicity because of a secondary effect on vesicle transport within the cell. That would explain some of the weirder results, but I'm not 100% on it. Methamphetamine appears to keep vesicles away from the synapse, while cocaine appears to lead to more vesicles being close to the synapse. Not sure if MPH could have the same effect as cocaine, but if so it might be a good idea to cycle AMP and MPH at least on paper...

This is very interesting... that sort of opposite behavior suggests to me involvement of DAT (downregulated by amph but upregulated by cocaine), which would make a lot of sense. (Maybe an attempt by the cell to maintain normal intracellular (non-vesicular) DA levels?) What are your thoughts on how this could affect toxicity?

 

[Amu]

Are there any agents that specifically prevent excitotoxicity besides memantine?

 

[atrollappears]

Are there any agents that specifically prevent excitotoxicity besides memantine?

You mean anything besides DXM or other voltage independent NMDA antagonists?
How about taurine? http://www.fasebj.org/content/18/3/511.full

 

[Amu]

Memantine at some unknown low-dose only blocks extra-synaptic NMDA receptors which are involved in neurotoxicity, leaving post-synaptic ones alone, the question is at what dosage does this occur in humans? I'm guessing around 20 mg, any estimates? Also, it is annoying how it blocks nicotine/acetylcholine's action on alpha-7 receptors otherwise it would be a great drug

 

[Epsilon Alpha]

Hey, been really busy with midterms lately.

From what I've seen in a few papers I'm mulling over is that stress breeds the kind of conditions for amphetamine neurotoxicity or negative aspects of sensitization to take place. There is also a lot more evidence piling for amphetamine sensitization sharing a similar foundation as schizophrenia or bipolar disorder.
http://www.ncbi.nlm.nih.gov/pubmed/18757738

 

[chaultistic]

Activation of glial cells is a specific marker for neurotoxicity, right? If so, then I'd look toward the metabolites. There's a very specific SAR for what does and does not cause neurotoxicity: amphetamines (not cathinones), but only amphetamines which can be para-hydroxylated (if I may extrapolate from 4-FA and conflate 5-HT and DA toxicity).



This is very interesting... that sort of opposite behavior suggests to me involvement of DAT (downregulated by amph but upregulated by cocaine), which would make a lot of sense. (Maybe an attempt by the cell to maintain normal intracellular (non-vesicular) DA levels?) What are your thoughts on how this could affect toxicity?

Is that necessarily a good thing to switch back and forth? Wouldn't you want upregulation instead of downregulation? Or are you trying to say if you're on AMPH and you get a tolerance, that going on cocaine/MPH will make the AMPH work better? Would this cause more or less damage to be switching, or is that something difficult to answer, even on paper?

 

[atrollappears]

Or are you trying to say if you're on AMPH and you get a tolerance, that going on cocaine/MPH will make the AMPH work better? Would this cause more or less damage to be switching, or is that something difficult to answer, even on paper?

Yes I think that's what he's saying. As far as amph 'neurotoxicity' goes, I don't know how this would affect it. However, if redistribution of VMAT were permanent and somehow negative (maybe increased parkinson's risk or something) then it could be considered a type of damage. So, if it is indeed a bad thing, which it very well may be, then this would be a way of causing less damage.

In general though, I'd caution against using oneself as a guinea pig to test things which are thus far only theories. Honestly, if you were to use non-meth amphetamine regularly and not become heavily dependent on it, without any supplements or whatever, it doesn't seem like it would really be that bad for you. Even if it does do a few mild negative things, I'd take that over potentially creating some terrible emergent side-effect which left me a retarded akinetic zombie.

 

[atrollappears]

Memantine at some unknown low-dose only blocks extra-synaptic NMDA receptors which are involved in neurotoxicity, leaving post-synaptic ones alone, the question is at what dosage does this occur in humans? I'm guessing around 20 mg, any estimates? Also, it is annoying how it blocks nicotine/acetylcholine's action on alpha-7 receptors otherwise it would be a great drug

Maybe huperzine, since its known to block excitotoxicity while being nootropic/not causing dissociation. Might not be a pharmacological specificity at NMDAR though so much as acetylcholinesterase inhibition.

 

[chaultistic]

I'm a little confused, I wasn't talking about methamphetamine. I was talking about regular amphetamine mix switched back and forth between cocaine/mph. Does levo/dextroamphetamine itself cause redistribution of VMAT?

*edit* I'm not very savvy about all this stuff, so bear with me on my questions.