Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

[atrollappears]

I've been thinking about the potential mechanisms behind amph DA neurotoxicity, and I've come up with a very speculative theory on the pathway. I haven't abandoned my hunch that the metabolism of the drug itself plays a role, so I began with that. So, (meth)amph is oxidized by MAO into something which is then necessary for damage to occur (since MAOIs are protective). Well, this metabolite is oxidated so it's probably an oxidant, especially when concentrated in nerve terminals, so glutathione possibly reacts to reduce this molecule. However, if the concentration of this metabolite is high enough to oxidize a significant portion of the glutathione, perhaps this disrupts glutathione's important natural reduction of nitric oxide (with reduced glutathione conc. NO becomes toxic at usually trophic levels). (Edit: Methamp-induced neurotoxicity seems to accelerate the oxidation of NADPH [probably because of oxidative conditions], which is required in reduced form to reclaim oxidized glutathione, likely further depleting glutathione's antioxidant efficacy.) Meanwhile, calcium influx from neuronal excitation induces the synthesis of NO. The resulting excess of NO could then activate microglia (with resulting oxidant/excitotoxin release aggravating the effect) and thereby cause cell damage, whether through apoptosis, necrosis, or whatever.

This accounts for several features of (meth)amp toxicity:
-Protection by MAOIs
-Partial protection by NMDA antagonists/induction of nitric oxide synthase
-Partial protection by antioxidants, since the oxidation would occur in a concentrated fashion in the nerve terminal, while with MDMA, whose toxicity is completely blocked by antioxidants, oxidative metabolites must diffuse through the periphery
-Specific neurotoxicity of non-keto amphetamines, due to specific metabolic pathways
-Reduction in glutathione observed in some studies, using sufficient dosages. Other studies find increases, but note that the depletion of glutathione need only occur in the nerve terminal, not everywhere, so to find a general increase in GSH doesn't mean it isn't being depleted where it counts.

Critiques?

 

[m060mm]

I'm a little over my head so bear with me:

My understanding is that DXM prevents the glutamatergic influx of calcium ions via voltage-gated agonist ligands. It does this by antagonizing the NMDAR.

Magnesium will have similar results, but will only prevent excess (abnormal, due to amphetamines) influx; it will not prevent the typical influx generated from an action potential. If this is correct, how does this work - the magnesium is blocking the calcium channel? So the NMDAR is agonized, it just has no effect of calcium gradients?

Assuming this (please correct me as necessary), what are the practical implications of this distinction?

 

[atrollappears]

I'm a little over my head so bear with me:

My understanding is that DXM prevents the glutamatergic influx of calcium ions via voltage-gated agonist ligands. It does this by antagonizing the NMDAR.

Magnesium will have similar results, but will only prevent excess (abnormal, due to amphetamines) influx; it will not prevent the typical influx generated from an action potential. If this is correct, how does this work - the magnesium is blocking the calcium channel? So the NMDAR is agonized, it just has no effect of calcium gradients?

Assuming this (please correct me as necessary), what are the practical implications of this distinction?

DXM blocks the NMDAR in a voltage independent fashion. Magnesium blocks the NMDAR in a voltage dependent fashion.
The implication of this is that when magnesium is present, normal cell signaling is preserved, whereas with DXM obviously it is not. So, magnesium will prevent excess Ca++ influx while preserving cognition, whereas DXM will not preserve cognition but block Ca++ influx more effectively.

 

[m060mm]

DXM blocks the NMDAR in a voltage independent fashion. Magnesium blocks the NMDAR in a voltage dependent fashion.
The implication of this is that when magnesium is present, normal cell signaling is preserved, whereas with DXM obviously it is not. So, magnesium will prevent excess Ca++ influx while preserving cognition, whereas DXM will not preserve cognition but block Ca++ influx more effectively.

Boom. Everything I needed. You're truly lovely. And I like your hair.

 

[eeklekins]

Phosphatidylserine acts directly on microglia to decrease the release of pro-inflammatory molecules. Because exactly that is believed to be a necessary step in the pathway of amphetamine neurotoxicity, phosphatidylserine supplementation could be extremely useful, and in any case I don't see it hurting.

http://journals.lww.com/jneuropath/...ion_of_Phosphatidylserine_Receptor_and.6.aspx

You'd be better off just taking fish oil. All the phosphatidylserine we need is readily synthesized in the body, and there's no real evidence showing a benefit from supplementation except for a few flawed studies by a sports supplement company.

 

[bremes]

What about 5-ht3 antagonists? I've heard they are neuroprotective. Ginger is wide available and is quite potent 5-ht3 antagonist.

 

[Epsilon Alpha]

What about 5-ht3 antagonists? I've heard they are neuroprotective. Ginger is wide available and is quite potent 5-ht3 antagonist.

5HT3 antagonists are a promising method of breaking sensitization, however its exact role hasn't been figured out. Mind posting some studies on the ginger 5HT3 antagonist bit though

 

[atrollappears]

5HT3 antagonists are a promising method of breaking sensitization, however its exact role hasn't been figured out. Mind posting some studies on the ginger 5HT3 antagonist bit though

What exactly is the problem with sensitization anyway? And why do researchers think its a useful model for schizophrenia/bipolar/addiction/basically everything they're trying to figure out? On paper, in humans, it looks pretty good to me. I wish I sensitized, I don't think I do :/

 

[atrollappears]

You'd be better off just taking fish oil. All the phosphatidylserine we need is readily synthesized in the body, and there's no real evidence showing a benefit from supplementation except for a few flawed studies by a sports supplement company.

I agree that fish oil is good, and I take it myself. However, for the same reason that the SSRIs superseded tryciclics I prefer to use the most pharmacologically specific agent to be sure that I am fully accomplishing what I want, and also not inadvertently causing some other potentially counterproductive effect. (Maybe SSRIs are a bad example... Imagine effective SSRIs xD)
Also, the literature does support phosphatidylserine.
For ADHD: http://www.whathealth.com/phosphatidylserine/references.html
For stress and mood: http://www.ncbi.nlm.nih.gov/pubmed/11842886
That it's more effective than fish oil: http://www.ajcn.org/content/87/5/1170.abstract

 

[Epsilon Alpha]

Well in ADHD individuals without a predisposition to addiction/depression/mania/OCD/psychosis its probably involved in the increased focus even after medication is withdrawn following long term treatment. But, in some individuals it may be involved in negative psychological changes and tics.

I'm mainly interested in it as a mechanism behind that "first time use" feeling most users report. Also, its just interesting as sin :D

 

[atrollappears]

From what I've read, people with ADHD who were medicated with ritalin in childhood, matched with people with ADHD who were not medicated, are virtually indistinguishable as adults besides having had a better experience in school while on the medication and having slightly higher self-esteem. So I'm doubtful about direct long-term benefit, if ritalin sensitization is analogous to amphetamine's.

I bet the first time thing has to do with that VMAT redistribution you mentioned
Edit: What do you mean by sensitization playing a role in that first time feeling? Are you suggesting that the development of sensitization blocks that feeling? That seems kind of counterintuitive considering sensitization increases feelings of "vigor" and "euphoria." Do you think, then, that the feeling is a function of drug reward, which does decrease even as sensitization develops? (Although I'd more readily ascribe that to classic tolerance.)

Also, are there any agents which increase the development of sensitization?

 

[Clickety]

NSAIDS as neuroprotective agents

Inflammation is thought to play a role in amphetamine toxicity as well.

What about NSAIDS such as ibuprofen taken before/during/after stimulant use to reduce or attenuate any neurotoxicity mediated by inflammation?

REF: http://www.ncbi.nlm.nih.gov/pubmed/18946735

 

[atrollappears]

Inflammation is thought to play a role in amphetamine toxicity as well.

What about NSAIDS such as ibuprofen taken before/during/after stimulant use to reduce or attenuate any neurotoxicity mediated by inflammation?

REF: http://www.ncbi.nlm.nih.gov/pubmed/18946735

Yup. We've talked about using aspirin in this thread before, but this study finds it ineffective so perhaps we should switch over to ibuprofen

Speaking of which, apparent anti-inflammatory effects of phosphatidylserine in vivo: http://ebm.rsmjournals.com/content/200/4/548.abstract

 

[Epsilon Alpha]

Inflammation is thought to play a role in amphetamine toxicity as well.

What about NSAIDS such as ibuprofen taken before/during/after stimulant use to reduce or attenuate any neurotoxicity mediated by inflammation?

REF: http://www.ncbi.nlm.nih.gov/pubmed/18946735

I don't think you realize how mind blowing that study is to me!

, these results imply that the protective effects of ibuprofen against METH-induced neurotoxicity may be based, in part, on its anti-inflammatory PPAR gamma agonistic properties, but not on its COX-inhibiting property or hypothermic effect.

I've been thinking that COX inhibition was one of the major pathways these drugs worked through, but I guess now its more of an artifact caused by the fact that most of the compounds I'm looking at inhibit it anyways. COX has previously been identified as a target for preventing DA cell damage in several studies, but I'll have to mull over more data to figure out exactly what is significant in preventing neurotoxic effects.

The author of that paper also has some earlier work on ketoprofen and it shows much the same promise.
http://www.ncbi.nlm.nih.gov/pubmed/14615038

 

[raybeez]

From what I've read, people with ADHD who were medicated with ritalin in childhood, matched with people with ADHD who were not medicated, are virtually indistinguishable as adults besides having had a better experience in school while on the medication and having slightly higher self-esteem. So I'm doubtful about direct long-term benefit, if ritalin sensitization is analogous to amphetamine's.

I'm going to assume that when you say "virtually indistinguishable", you're talking about behavioral metrics. The reason for this finding is because ADHD persistence into adulthood is very low - only 40% of children with ADHD continue to have symptoms, and only 0.9% of children meet the full diagnostic criteria as adults [1].

Interestingly this decline in ADHD rates is only seen on behavioral studies - these former children with ADHD still have abnormal brain scans [2]. Afiak there haven't been studies looking at the effect of ritalin use as a child on brain scans in adults, which would be the type of study needed to properly back up that claim you cite.

 

[atrollappears]

Interestingly this decline in ADHD rates is only seen on behavioral studies - these former children with ADHD still have abnormal brain scans [2]. Afiak there haven't been studies looking at the effect of ritalin use as a child on brain scans in adults, which would be the type of study needed to properly back up that claim you cite.

As far as I'm concerned, how the brain looks on a brain scan only matters insofar as it affects the physical or psychological well-being of the person.

Also, I don't know if I've mentioned this before, it's probably a good idea to avoid too much caffeine while using amphetamine (especially if using it recreationally). Here's a source, and I'd love if someone could get me full access: http://jpet.aspetjournals.org/content/271/3/1320.short

Edit: Almost forgot to mention, the flipside of this is that regular caffeine use is protective against amphetamine neurotoxicity because of tolerance mechanisms, as long as you have allowed time for the caffeine to leave your body before taking an amphetamine.

 

[atrollappears]

Evidence that you should eat healthy, trans fat increases neurotoxicity and fish oil (unsaturated) decreases it:
http://www.sciencedirect.com/science/article/pii/S0091305710003424

Fish oil itself is a concern if oxidized, but it looks like the gelcaps are OK:
http://www.ncbi.nlm.nih.gov/pubmed/22101881

The unknown level of oxidation in available fish oil products is a concern, but regularly buying small quantities in gelcaps from a reputable manufacturer would ensure maximum freshness.

 

[bremes]

D2 agonists seems to be neuroprotective.

Biochem J. 2003 Jul 1;373(Pt 1):25-32.
Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines.
Nair VD, Olanow CW, Sealfon SC.
Source

Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Abstract

Whereas dopamine agonists are known to provide symptomatic benefits for Parkinson's disease, recent clinical trials suggest that they might also be neuroprotective. Laboratory studies demonstrate that dopamine agonists can provide neuroprotective effects in a number of model systems, but the role of receptor-mediated signalling in these effects is controversial. We find that dopamine agonists have robust, concentration-dependent anti-apoptotic activity in PC12 cells that stably express human D(2L) receptors from cell death due to H(2)O(2) or trophic withdrawal and that the protective effects are abolished in the presence of D(2)-receptor antagonists. D(2) agonists are also neuroprotective in the nigral dopamine cell line SN4741, which express endogenous D(2) receptors, whereas no anti-apoptotic activity is observed in native PC12 cells, which do not express detectable D(2) receptors. Notably, the agonists studied differ in their relative efficacy to mediate anti-apoptotic effects and in their capacity to stimulate [(35)S]guanosine 5'-[gamma-thio]triphosphate ([(35)S]GTP) binding, an indicator of G-protein activation. Studies with inhibitors of phosphoinositide 3-kinase (PI 3-kinase), extracellular-signal-regulated kinase or p38 mitogen-activated protein kinase indicate that the PI 3-kinase pathway is required for D(2) receptor-mediated cell survival. These studies indicate that certain dopamine agonists can complex with D(2) receptors to preferentially transactivate neuroprotective signalling pathways and to mediate increased cell survival.

Memantine, Ketamine and probably Methoxetamine are D2 agonists.

 

[Epsilon Alpha]

Atrollappears, mind summing up that childhood stimulant treatment paper you got yesterday? I'm interested in the findings

 

[atrollappears]

Atrollappears, mind summing up that childhood stimulant treatment paper you got yesterday? I'm interested in the findings

The stimulant treated kids were basically the same as untreated kids, but were more emotionally healthy, had better self-esteem, and a better view of their childhoods.
I saw no evidence of increased depressed/anxious behavior like that seen with rats treated with MPH in childhood; if anything, it was the opposite.

Edit: Forgot to mention, the stimulant treatment was exclusively MPH, so I guess the study is relevant to amphetamine only insofar as you're looking at long-term effects that are exclusively the consequence of elevated DA/NE.