Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

[arohydro]

Amphetamine is pretty benign, honestly. AFAIK well-controlled studies haven't found any negative effects (maybe slight positive ones) of even recreational amphetamine use... and there are a bunch of reasons I could give you for why neurotoxicity found in rodent studies is unlikely to apply to any reasonable human use. Amphetamine has been around a long time, so it's pretty safe to assume that its risks have been documented.

Do you mind sharing those reasons? Or linking me to some studies conducted? I can only find megadoses given to rats.

Being convinced does more for my mind than reassurance. : )

 

[MeDieViL]

That doesnt mean its not neurotoxic you just wont notice negatives as you need to destroy a shitload of da neurons to start shaking around as a parkinson guy, seems that its hard to get there.

 

[Tussmann]

Do you mind sharing those reasons? Or linking me to some studies conducted? I can only find megadoses given to rats.

Being convinced does more for my mind than reassurance. : )

If we are including all amphetamines here -- meth in particular -- megadosing addicts barely harness smiles and laughs even with 10 years of cession. Literal DA destruction in the reward pathway.

Call it extreme and chronic receptor downregulation if you want but honestly its still doing permanent debilitating effects.

 

[arohydro]

If we are including all amphetamines here -- meth in particular -- megadosing addicts barely harness smiles and laughs even with 10 years of cession. Literal DA destruction in the reward pathway.

Call it extreme and chronic receptor downregulation if you want but honestly its still doing permanent debilitating effects.

Precisely my point; I'd like to AVOID that, even in very, very small doses of anhedonia. I have a history of depression and attentive issues, no reason to exacerbate them. I am afraid that should I utilize adderall, later on in life I might be far worse off than I am now as it's more of a band-aid. Right now, my goal is to be completely medication free. If I use medication to get me halfway there, then it's much easier to finish.

We don't know how long we'll be living in the future, I'd like to save all of my dopamine for later in life if possible. Maybe you say, as a consequence, 'just don't fool with amphetamines.' Fine with me, but it's cool to see proof, see studies, see interpretations. Understand why, for instance, rat studies might not be applicable to humans. Where the 'threshold', if any, for neurotoxicity exists, and how to avoid crossing it. If that's finnicky, then how you can protect against damage assuming that the threshold will sometimes be crossed in order to mitigate long-term risk.

 

[Woundrous]

http://en.wikipedia.org/wiki/D2-like_receptor
D2, D3, and D4 all inhibit cAMP formation.

This is nonsense. You do not know what you are posting about.

 

[MeDieViL]

He does, its just a bit complicated pal:

Two intracellular signaling pathways for the dopamine D3 receptor: opposite and synergistic interactions with cyclic AMP.
Griffon N, Pilon C, Sautel F, Schwartz JC, Sokoloff P.
Source
Unité de Neurobiologie et Pharmacologie, Centre Paul Broca de l'INSERM, Paris, France.
Abstract
As cerebral neurons express the dopamine D1 receptor positively coupled with adenylyl cyclase, together with the D3 receptor, we have investigated in a heterologous cell expression system the relationships of cyclic AMP with D3 receptor signaling pathways. In NG108-15 cells transfected with the human D3 receptor cDNA, dopamine, quinpirole, and other dopamine receptor agonists inhibited cyclic AMP accumulation induced by forskolin. Quinpirole also increased mitogenesis, assessed by measuring [3H]thymidine incorporation. This effect was blocked partially by genistein, a tyrosine kinase inhibitor. Forskolin enhanced by 50-75% the quinpirole-induced [3H]thymidine incorporation. This effect was maximal with 100 nM forskolin, occurred after 6-16 h, was reproduced by cyclic AMP-permeable analogues, and was blocked by a protein kinase A inhibitor. Forskolin increased D3 receptor expression up to 135%, but only after 16 h and at concentrations of > 1 microM. Thus, in this cell line, the D3 receptor uses two distinct signaling pathways: it efficiently inhibits adenylyl cyclase and induces mitogenesis, an effect possibly involving tyrosine phosphorylation. Activation of the cyclic AMP cascade potentiates the D3 receptor-mediated mitogenic response, through phosphorylation by a cyclic AMP-dependent kinase of a yet unidentified component. Hence, transduction of the D3 receptor can involve both opposite and synergistic interactions with cyclic AMP.

 

[Cloudy]

I'm pretty sure that D2 like receptors [D2, D3 ( though it can be weaker at this as to not be very detectable), and D4 receptors] inhibit AC via g-protien coupled receptors which leads to a negatively regulate production of cAMP which result in a decrease in activity of PKA, and a decrease in DARPP-32 phosphorylation. Through other mechanisms involving an increase of intercellular Ca+ by D2 like receptors, there is an increase of dephospho-DARPP-32 leading to a decrease in DARPP-32 phosphorylation as well. So from what I understand, he's not really completely wrong. If you have critique why don't you post something of more substance to enlighten us to help use better understand why he may be wrong.

 

[Epsilon Alpha]

This is nonsense. You do not know what you are posting about.

Do you have evidence to the contrary? Excitatory vs inhibitory neurotransmission goes a lot further than increasing/decreasing [cAMP].

 

[MeDieViL]

What is your opinion on MB epsilon alpha? as it depletes glut and no it should theoretically do what we want here but it seems some receptors take over the job such as LTP, so tolerance may still occur due to a diff mechanism but thats a gues.

 

[Woundrous]

Ok sorry my bad, I did not click the links. I just opened the first page and it didn't say much. I need to refresh my class A GPCR signal transduction knowledgebank. =(

Anyways, my underlying point is that I've had huge personal success adding creatine malate into my regimen to prevent brain zaps from using MXE/6APB too much. I don't know exactly why it is working so well, just that it is helping a damn lot (enough to get me to rejoin the forum to post about it!), but you'd think ATP has to be the reason. So I was thinking it could possibly be of use for long-term amphetamine users too.

But of course, people would have to try it out first...

 

[MeDieViL]

Creatine and atp are anticonvulsant, sero is implicated in epileptic activity thats why after abusing serotogenics you get mild seizure activity mainly by 5HT2C downregulation.

 

[Woundrous]

Thanks that's an interesting idea. If we can actually nail that down as a mechanism, this type of information should be added to something regarding harm reduction. So probably it would only work for stuff like 6APB and MDMA then... also probably serotonergic antidepressants (which I have seen people mention getting brain zaps from). I'm not sure about LSD or any 2C-whatever. I never got zaps from those, just MDMA and the 6APB/MXE combo (I always combine them) but I have never really used LSD/2C-X on consecutive nights for consecutive weekends either.

I'm actually a bit surprised there is not a general harm reduction guide for this site on the front page or something. I mean, that is supposed to be a primary point of this place anyways; general harm reduction strategies for drug classes. A quick and easy "what to do" type guide on the front page that is easily noticeable would be sweet for people to have easy access to I think.

I'd probably volunteer to get it started... but I am clueless about stuff like heroin/opiate harm reduction, if there even is anything besides having a healthy lifestyle and not getting yourself addicted.

 

[amanitadine]

I think a better approach to harm reduction is not take 6-apb and methoxetamine "weekend in and weekend out" rather than some virtually baseless conjecture and subjective reasoning that creatine ameliorates the damage caused by such. Two very unstudied drugs that are obviously hard on the body when taken once, let alone repeatedly.

 

[MeDieViL]

Thanks that's an interesting idea. If we can actually nail that down as a mechanism, this type of information should be added to something regarding harm reduction. So probably it would only work for stuff like 6APB and MDMA then... also probably serotonergic antidepressants (which I have seen people mention getting brain zaps from). I'm not sure about LSD or any 2C-whatever. I never got zaps from those, just MDMA and the 6APB/MXE combo (I always combine them) but I have never really used LSD/2C-X on consecutive nights for consecutive weekends either.

I'm actually a bit surprised there is not a general harm reduction guide for this site on the front page or something. I mean, that is supposed to be a primary point of this place anyways; general harm reduction strategies for drug classes. A quick and easy "what to do" type guide on the front page that is easily noticeable would be sweet for people to have easy access to I think.

I'd probably volunteer to get it started... but I am clueless about stuff like heroin/opiate harm reduction, if there even is anything besides having a healthy lifestyle and not getting yourself addicted.

lol, its a complete failure at that, the advice of using memantine for tolerance issues should be all over the place, the use of neuroprotection, dont really see the point of brainzaps tough they are just extremely anoying, especially when you add g to it as that is a bit convulsive inducing.

I posted a complete list of meds somewhere once that reduce addiction, also its stupid ppl dont even have a clue that ordering a couple of xanax theyd never have to worry about accidently running out of g. That said the g neurotoxiticy data should be spread out more i had to post it here after reading it on drugs forum, everyone tought it was harmless.

 

[MeDieViL]

I think a better approach to harm reduction is not take 6-apb and methoxetamine "weekend in and weekend out" rather than some virtually baseless conjecture and subjective reasoning that creatine ameliorates the damage caused by such. Two very unstudied drugs that are obviously hard on the body when taken once, let alone repeatedly.

Where talking about harm reduction not harm avoidance, then you might as well say never take drugs, eat healthy and go to bed early.

PPl allways go very far, so saying something like "dont do that" if its extremely bad wont help, but some things that limit the damage can.

 

[Epsilon Alpha]

What is your opinion on MB epsilon alpha? as it depletes glut and no it should theoretically do what we want here but it seems some receptors take over the job such as LTP, so tolerance may still occur due to a diff mechanism but thats a gues.

I don't really have much time between my job, medschool applications, classes, and my charity work; mind posting relevant links towards its pharmacology? It looks decent at first glance, as do PQQ and lithium, but we really need trials to be done before we can say anything but "looks promising".

 

[campers]

Mean to post this up a while ago. A couple have already been posted but here's a nice list of studies I found, focused on glutathione, but also some on Vit C, Selenium (required for glutathione enzymes) and Nrf2 (a whole topic in itself).

NAC = N-Acetyl-Cystine
(fyi there is a better cysteine pro-drug than NAC available now, and also an acylated form of glutathione)

http://www.ncbi.nlm.nih.gov/pubmed/3992009

Pretreatment with 100.0 mg/kg of ascorbic acid 30 minutes before each methamphetamine injection significantly (but not completely) attenuated this neurotoxic action of methamphetamine.

http://www.ncbi.nlm.nih.gov/pubmed/15199373

These results suggest that NAC could attenuate the reduction of DAT (dopamine transporter ) in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/?tool=pubmed

The idea that oxygen-based free radicals are involved in METH neurotoxicity is further strengthened by reports that the drug can reduce the levels of glutathione

http://www.ncbi.nlm.nih.gov/pubmed/9839724

Our observations provide further evidence in support of the oxidative stress hypothesis of MA neurotoxicity and indirectly suggest that drugs designed to increase glutathione might protect against such damage.

http://www.ncbi.nlm.nih.gov/pubmed/10642830

We have shown that dietary Selenium attenuated methamphetamine neurotoxicity and that this protection involves Glutathione Peroxidase-mediated antioxidant mechanisms

http://www.ncbi.nlm.nih.gov/pubmed/10650149

These data suggest that METH-induced neurotoxicity is mediated by the production of peroxynitrite, and selenium plays a protective role in METH-induced neurotoxicity.

http://www.ncbi.nlm.nih.gov/pubmed/10913590

These findings indicate selectivity of methamphetamine for the glutathione system and a role for methamphetamine in inducing oxidative stress.

http://www.ncbi.nlm.nih.gov/pubmed/12018843

METH toxicity seems to be produced by oxidative stress, as it was attenuated by the antioxidant glutathione

http://www.ncbi.nlm.nih.gov/pubmed/21882243

We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons

http://www.ncbi.nlm.nih.gov/pubmed/11746378

A dose-dependent depletion of total glutathione levels was detected in human brain microvascular endothelial cells exposed to METH

http://www.ncbi.nlm.nih.gov/pubmed/12230306

These results suggest that METH-induced disturbances in cellular redox status and that activation of AP-1 can play a critical role in signaling pathways leading to upregulation of inflammatory genes in vivo

http://www.ncbi.nlm.nih.gov/pubmed/15234256

These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

http://www.ncbi.nlm.nih.gov/pubmed/15111252

It was found that acute administration of methamphetamine (5 and 15 mg kg(-1)) resulted in production of oxidative stress as demonstrated by decreased glutathione and increased oxidized glutathione levels

http://www.ncbi.nlm.nih.gov/pubmed/16038959

Enantiomers of trans-phenylpropylene oxide (Pyrolytic products of smoked methamphetamine) were stereoselectively and regioselectively conjugated in a Phase II drug metabolism reaction catalyzed by human liver cytosolic enzymes consisting of conjugation with glutathione

http://www.ncbi.nlm.nih.gov/pubmed/16760923

The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of conditioned place preference training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls.

http://www.ncbi.nlm.nih.gov/pubmed/22354084

This suggests that METH induces oxidative stress in various organs and that a combination of N-acetylcysteine amide as a neuro- or tissue-protective agent, in conjunction with current treatment, might effectively treat METH abusers.



http://www.ncbi.nlm.nih.gov/pubmed/17481858 Glutathione prevented dopamine-induced apoptosis of melanocytes and its signaling.

"Among various antioxidants used in this study, only thiol-containing antioxidants such as NAC or GSH inhibited both JNK and p38 MAPK activation and apoptosis, indicating the unique protective capacity of thiol compounds."

 

[polarbearsarecool]

My latest stack-which I've found the greatest results with has been

1/3 nuvigil 250 before wakeup
1/3 nuvigil 250 at wakeup-----> directly at wakeup take 1 source naturals activated quercetin, 250mg uridine monophosphate sublingual, 30 minutes later with food take 200-400mg nefiracetam/idebenone 500mg-1g/ Omega 3 EPA/DHA 2200mg..
1/3 nuvigil 250 4/5 hours later

and continue nefiracetam 2x more times in the day, as well as 1x omega 3, and another uridine dose..

Idebenone is a powerful antioxidant that also has NGF releasing capabilities...

But for amph tolerance quercetin/uridine.... HUGE CHANGE.

PQQ though, is not that good. I used it and went through 2 bottles, eventually my thoughts became slurried, and I realized my memory was taking a hit because I was combining it with 4+ other PDE inhibitors, now with just quercetin/nuvigil, it still has a slurry effect..

PQQ is a quinone just like quercetin, just hugely overpriced.

 

[Epsilon Alpha]

Wow, I really need to get back to this thread.
Work. So. Busy. Med. School. Apps.

For what its worth my personal experience over the last year with 10-20mg Adderall 3-5 times a week scripted for a sleep disorder:

• CoQ10: preserves wake promoting effects, as well as anorexic effects
• Magnesium: preserves a bit of the mood lift, biggest effect for me was on neck tension
• Multivitamin: I feel much more groggy if I skip 2 days of multivitamin
• Vitamin D: Increases wakefulness, not too significant but for someone like me it's a noticeable difference.
• Curcumin (for 2 weeks): My GIT did not like this... I used it during a tolerance break and upon using my perscription found it significantly reduced the tolerance to the motivational effects, mood lift was moderately increased over what I would expect for a 2 week break, no real difference with wakefulness over what I would expect, significant increase in anorexic effects.

Been doing some digging through some obscure NOS/transcriptional changes lately, and I'm slowly finding why several studies have identified continued cell death for up to 2 weeks in rat models. What are possible implications of that? Well it would suggest that longer post loading for recreational users might be a good idea.

 

[Tussmann]

Well it would suggest that longer post loading for recreational users might be a good idea.

Could you expand on this a bit? I have no idea what this means.