Magnesium and Amphetamine Neurotoxicity

[atrollappears]

I am very confused about the role magnesium plays in striatal oxidative/excitotoxic neurotoxicity. This is very relevant because many amphetamine users take magnesium supplements to reduce/maintain tolerance.
Studies with MPTP/MPP toxicity (closely related to amphetamine toxicity, I believe) show very different results. In a study with mice, Mg in drinking water increased the dopaminergic neurotoxicity of a high (lethal to some mice) dose of MPTP. In another study, however, mice deficient in Mg were more vulnerable to the dopaminergic neurotoxicity of a low (not toxic to non-Mg-deficient) dose of MPTP. Two other studies showed evidence for a protective role for magnesium on striatal cells in vitro, one finding a lack of irreversible MPTP-induced inhibition of synaptic transmission using a low Ca/high Mg cerebrospinal fluid, and the other observing striatal cells directly and finding that a high concentration of Mg completely prevented the loss of dopaminergic cells due to MPP.
So, what the hell? Can anyone explain this? The first study I mentioned attempted to explain the discrepancy by saying that Mg can be a weak Ca agonist, and they then alluded to this study http://www.sciencedirect.com/science/article/pii/0091305790901207 which they say shows that amphetamine neurotoxicity is increased by Mg. I would be grateful for anyone who can provide the link to the PDF of this study.
Here are the links to the other studies I mentioned, PDF for the first one:
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0773.1998.tb01428.x/pdf
http://www.sciencedirect.com/science/article/pii/S0168010208002629
http://www.sciencedirect.com/science/article/pii/000689939191035Y
http://www.sciencedirect.com/science/article/pii/S000689930702971X

 

[Epsilon Alpha]

Interesting, it almost looks like a U-shaped curve for magnesium levels and MPTP induced toxicity. The first study you posted used very high levels of magnesium which is more of a voltage dependent antagonist at the NMDA receptor (natural channel blocker) at "normal" ranges, but the weak agonist at high concentrations point is news to me. Could it be a osmotic thing?

If it is just a case of lower [Mg2+]=antagonist at NMDA and higher [Mg2+]=agonist, then it would be interesting to see what levels humans who supplement magnesium reach. However, it could also possibly involve really dirty downstream pathways aside from NMDA that would make this a bit more difficult to figure out.

 

[atrollappears]

Well since magnesium supplementation, like NMDA antagonists, reduces/blocks amphetamine tolerance, then is it reasonable to assume that magnesium in supplement doses is acting as an NMDA antagonist? I'm pretty sure that studies have implied that magnesium's effect of increasing amphetamine induced hyperlocomotion and such is due to its action as an NMDA antagonist, though I could be wrong.
And what do you mean by osmotic thing/dirty downstream pathways?

Edit: For "osmotic thing," do you mean that Mg itself could be diffusing through the cell membrane? I assume that would be a concentration way higher than those seen in human magnesium supplementation...

 

[Epsilon Alpha]

Tons of intracellular proteins use magnesium and it binds to almost every negatively charged molecule in the cell, from ATP to DNA so if the increased toxicity of MPTP is not solely due to NMDA mediated effects, then things get messy trying to figure out what is going on.
As far as osmosis, if the extracellular concentration of Mg2+ is much higher than the intracellular concentration MPTP might be able to allow Mg2+ to force its way into the cell via osmotic pressure. But, that's a long shot.

 

[atrollappears]

Ah okay. Well what do you think this says about the safety of magnesium supplementation? Do you think it's likely that human supplementation reaches levels that could Increase the toxicity of amphetamine? I know it's hard to say based on such limited information, but your guess is better than mine.

I still wish I could get my hands on that study that actually uses amphetamine...

 

[Epsilon Alpha]

I'd hazard a guess that its below what humans can reach with reasonable supplementation, as magnesium has a notoriously poor bioavailability in most cases. We still have a body of evidence suggesting that most westerners are deficient in magnesium and that deficiency is linked to increased neurotoxic effects of amphetamine.

Still the highest doses of magnesium they posted are pretty much only reachable by drinking epsom salt bath water every day. But, the calcium agonist bit is very very interesting.

I'd do some more research but I'm procrastinating hard enough from my term paper as is.

 

[tyrael]

Very interesting thread Blers! Thanks!

....
assume that magnesium in supplement doses is acting as an NMDA antagonist?
...

If this is the case, it would be interesting to see to which degree is exhibits this behaviour. Also this would imply that by pre-loading or concurrently dosing Mg with Amphets, would effect (negativity) the expected results. No?

....
I'd do some more research but I'm procrastinating hard enough from my term paper as is.

Prioritise study over BL!!.....however I wouldn't mind reading whatever papers you may have regarding this theory!

 

[atrollappears]

If this is the case, it would be interesting to see to which degree is exhibits this behaviour. Also this would imply that by pre-loading or concurrently dosing Mg with Amphets, would effect (negativity) the expected results. No?

Well, Mg's function in the brain is to act as a voltage-dependent NMDA antagonist. So, it blocks the NMDA receptor so no Ca can get through until a certain voltage is achieved in the cell, which then pushes the Mg out. Studies show that concurrent Mg administration amplifies the effect of amphetamine. However, as far as chemical NMDA antagonists, more conflicting studies:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908186/pdf/brjpharm00238-0207.pdf
http://www.sciencedirect.com/science/article/pii/036192309290034U
http://www.sciencedirect.com/science/article/pii/S0006322300009768
http://www.sciencedirect.com/science/article/pii/009130579490295X

Thanks Epsilon Alpha. Can you provide a link to research showing magnesium deficiency contributes to amphetamine neurotoxicity?

 

[Amu]

Well, Mg's function in the brain is to act as a voltage-dependent NMDA antagonist. So, it blocks the NMDA receptor so no Ca can get through until a certain voltage is achieved in the cell, which then pushes the Mg out. Studies show that concurrent Mg administration amplifies the effect of amphetamine. However, as far as chemical NMDA antagonists, more conflicting studies:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908186/pdf/brjpharm00238-0207.pdf
http://www.sciencedirect.com/science/article/pii/036192309290034U
http://www.sciencedirect.com/science/article/pii/S0006322300009768
http://www.sciencedirect.com/science/article/pii/009130579490295X

Thanks Epsilon Alpha. Can you provide a link to research showing magnesium deficiency contributes to amphetamine neurotoxicity?

Wouldn't magnesium's NMDA antagonist properties reduce the effectiveness of amphetamine? It would reduce glutamate signaling across a range of areas, reducing neuronal firing of dopamine-mediated receptors, sure it's neuroprotective against over-excitation but that isn't the purpose here. It would be similar to taking dopamine antagonists to perhaps up-regulate receptors, I guess NMDA antagonism could be useful during amphetamine holidays. This is similar to memantine being used for OCD and amphetamine tolerance/neurotoxicity, it will simply reduce firing across broad areas. I think an alpha-2 adrenoreceptor agonist like guanfacine could help reduce the needed dose for AMP, but apparently this is some evidence of this causing depression, remeron is another option, it's antagonism of 5-HT(2C) receptors is supposed to dis-inhibit DA/NE release, but it's an alpha-2 receptor antagonist, which will decrease AMP's effects perhaps, but it is also neuroprotective through 5-HT(3) antagonism.

EDIT: Typo correction, I meant guanfacine as the agonist, and remeron as the antagonist

 

[atrollappears]

One might expect that, but it doesn't seem to be the case. Supposedly AMP *tolerance* is due to excessive Ca influx through the NMDA receptor. Also, it doesn't seem that amphetamine exerts its primary effects directly through NMDA mechanisms, because as a couple of the studies I linked show, amphetamine DA release occurs in spite of, or is even amplified by, NMDA antagonists. The mentally-dulling effects of voltage independent NMDA block may take away from some of the desired effects of amphetamine, but this doesn't seem to be the result of directly inhibiting any primary mechanism of amphetamine.

Also, a few other points, guanfacine is actually an alpha-2a agonist. The interesting thing is that it alpha-2 ANTagonists actually decrease the behavioral effects of amphetamine, despite increasing DA/NA/5-HT release.

Edit: Scratch that last part. Alpha 2a antagonists increase the behavioral response to amphetamine but decrease sensitization. (Interesting as NMDA antagonists increase dopamine release but block sensitization.) Also, ADHD that does not respond to d-amphetamine is correlated with low alpha 2a receptor densities.

 

[atrollappears]

Also, off topic to the thread but relevant to your point about the alpha 2a receptor: I have experience taking d-amphetamine before and after being on a high dose of guanfacine, and once tolerance to side effects was developed, there was little difference if any in behavioral response.

 

[Amu]

One might expect that, but it doesn't seem to be the case. Supposedly AMP *tolerance* is due to excessive Ca influx through the NMDA receptor. Also, it doesn't seem that amphetamine exerts its primary effects directly through NMDA mechanisms, because as a couple of the studies I linked show, amphetamine DA release occurs in spite of, or is even amplified by, NMDA antagonists. The mentally-dulling effects of voltage independent NMDA block may take away from some of the desired effects of amphetamine, but this doesn't seem to be the result of directly inhibiting any primary mechanism of amphetamine.

Ah yes, so then the question is which NMDA antagonists are the least mentally dulling? It would be correlated with their de-sensitizing ability though, and I've read quite a few negative reports about memantine causing cognitive side effects, even at doses below 20mg/day.

Also, a few other points, guanfacine is actually an alpha-2a agonist. The interesting thing is that it alpha-2 ANTagonists actually decrease the behavioral effects of amphetamine, despite increasing DA/NA/5-HT release.

Ah yes, I mixed up the two when I wrote my post, by which mechanism do alpha-2-antagonists increase DA/NA release? I know 5-HT(2C) antagonists do this.

Also, ADHD that does not respond to d-amphetamine is correlated with low alpha 2a receptor densities.

I've suspected this is the case, as well as reduced grey matter density, which I guess is alpha-2 receptor density in the PFC, thus I think ADHD unresponsive to d-amp might be responsive to d-methamp, as I'm not convinced of d-amp's dopamine RELEASING properties despite the very close EC50 at low doses at least, and even then it isn't even close to d-methamp. In order to reverse the DAT at low doses, I think only d-methamp is capable of this, with (+) 2-fluoroamphetamine and (+) 2-fluoromethamphetamine being two very interesting alternatives, the latter not having history of experimentation with yet.

Also, off topic to the thread but relevant to your point about the alpha 2a receptor: I have experience taking d-amphetamine before and after being on a high dose of guanfacine, and once tolerance to side effects was developed, there was little difference if any in behavioral response.

I found this to be the case as well, I assume you received no benefit with guanfacine? I was quite shocked when it had no beneficial effects despite the positive studies. I've also not found NRIs (Strattera, Desipramine, Wellbutrin) to be helpful despite how they should indirectly increase PFC DA levels.

 

[atrollappears]

Alpha 2a receptors function as autoreceptors I think.

As far as the efficacy of d-amp in ADHD goes, I always assumed that whether the inattention/hyperactivity responds to d-amp depends on whether the ADHD itself was related to underactivation of the DA or the cortical NE system.
For me, d-amphetamine increases the "tunnel-vision" quality of my focus, but actually makes me even worse at properly directing my focus. My focus never lacked that tunnel-vision quality in the first place, so I don't respond to d-amphetamine with increased focus. An erowid trip report I read on desoxyn reported that it was even worse than d-amp in that respect, so I doubt that DA release is really the issue in d-amphetamine non-responsiveness. I'd put the blame more on NE.
I do actually receive benefit from guanfacine. It helps calm down my excess, distracting thoughts. However, I admit it's not the most efficacious medicine for ADHD I've tried. I do find that it is very helpful for a lot of things that are not ADHD: my taking guanfacine has correlated with decreased social anxiety and increased social ability, better blood pressure, more restful sleep, and improved appetite. Probably the most efficacious ADHD medicine for me is ritalin, though it always turned me into a zombie. I'd like to try it again now that I'm a young adult, since paradoxical sedation from stimulants decreases in severity with age. And, I attribute a lot of guanfacine's lack of efficacy to alpha 2a autoreceptor-mediated stemming of NE release (which logically would limit guanfacine's ability to stimulate the alpha 2a receptor), so it would be interesting to see how its efficacy would improve with a medication which acts primarily on NE, like low dose ritalin. Studies are very positive on guanfacine combined with stimulants.

But we should continue this conversation in private messages because it's not really relevant to the thread.