Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

[Epsilon Alpha]

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2009.05911.x/full Glutamate receptors do not change in rat NAcc during sensitzation
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202508/ Role of changes in glutamate systems in stimulant treatment (good old review)

 

[atrollappears]

Epsilon Alpha, or anyone else who can provide an answer, how much do we know about the mechanism behind amphetamine (DA) toxicity? Also, what is the speculated role of nitric oxide, and how might amphetamines generate it? I ask because nitric oxide synthase knockout is the only thing I've seen that can actually completely block neurotoxicity (besides blocking the DAT), so it seems pertinent.

 

[processofmind]

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


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

i also find this very interesting as well the study Epsilon Alpha posted on stimulant induced glutamate changes and plasticity. curcumin seems to hit many angles on this, iNOS inhibition, cox inhibition, NMDA antagonist.

 

[atrollappears]

i also find this very interesting as well the study Epsilon Alpha posted on stimulant induced glutamate changes and plasticity. curcumin seems to hit many angles on this, iNOS inhibition, cox inhibition, NMDA antagonist.

Except COX inhibition apparently isn't helpful, and iNOS inhibition might block the effects of amphetamine.

 

[kfluxsake]

I'd like to thank the contributors to this thread for doing such a wonderful job. As a smoker, I'd also like to add this study.

Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin

Karine Paraina, 1,
Céline Hapdeya, 1,
Estelle Rousseleta,
Véronique Marchandb,
Bernard Dumeryb,
Etienne C Hirscha,

Abstract

Epidemiological studies have found a negative association between cigarette smoking and Parkinson’s disease (PD). In order to analyze the putative neuroprotective effect of cigarette smoke and nicotine, one of its major constituents, we examined their effects in an animal model of PD provoked by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. Two groups of mice were chronically exposed to cigarette smoke (a low exposure subgroup and a high exposure subgroup; 5 exposures per day at 2-h intervals), two other groups received nicotine treatment (two doses tested 0.2 and 2 mg/kg, 5 injections i.p. per day at 2-h intervals) and one group placebo. On day 8 after the beginning of the treatment, 4 injections of MPTP hydrochloride (15 mg/kg, i.p., at 2-h intervals) or saline were administered to these animals. Nicotine and cotinine plasmatic concentration was quantified by the HPLC method, and degeneration of the nigrostriatal system was assessed by tyrosine hydroxylase (TH) immunohistochemistry. The loss of dopaminergic neurons induced by MPTP in the substantia nigra was significantly less severe in the chronic nicotine treatment groups (at 0.2 and 2 mg/kg) and the low exposure to cigarette smoke group than in the high exposure to cigarette smoke subgroup and the placebo treated subgroup. In contrast, no preservation of TH immunostaining of nerve terminals was observed in the striatum in any group. This suggests that nicotine and low exposure to cigarette smoke may have a neuroprotective effect on the dopaminergic nigrostriatal system by an as yet unknown mechanism.



http://www.sciencedirect.com/science/article/pii/S0006899303031950

 

[Dysphoric]

I read somewhere that Methamphetamine at lower doses can actually be neuroprotective. After looking around I found this http://www.ncbi.nlm.nih.gov/pubmed/21635908

I'm curious just how low of a dose is considered neuroprotective, would anywhere from 10-25mgs be in this area?

I'm mainly curious because I've been reluctant on taking Desoxyn, but after hearing this I might get back into taking it every so often.

 

[ShAYZoN]

If it was Nero protective I'd be inclined to take it again as well lol.

 

[Epsilon Alpha]

Epsilon Alpha, or anyone else who can provide an answer, how much do we know about the mechanism behind amphetamine (DA) toxicity? Also, what is the speculated role of nitric oxide, and how might amphetamines generate it? I ask because nitric oxide synthase knockout is the only thing I've seen that can actually completely block neurotoxicity (besides blocking the DAT), so it seems pertinent.

Well its a very multifaceted issue, particularly the toxicity that is observed days after last administration. But, this excerpt from the ketoprofen paper does a good job of explaining some of nitric oxide's acute effects.

In a previous report, we showed that METH injections (×4 with 2 h-interval) caused dose-dependent activation of striatal NF-κB which is a transcription factor activated by ROS, and that the activation of NF-κB was significantly attenuated in Cu,Zn-SOD-Tg mice [2]. NF-κB promotes induction of iNOS to generate NO, and consequently induce inflammatory cytokines. The generation of NO is involved in METH-induced neurotoxicity in dopaminergic neurons [11] and [12]. NSAIDs exert inhibitory effects against inflammatory mediators-induced increases in NF-κB and iNOS activities, to inhibit NO production [1] and [8]. It is well known that activated microglial cells produce various inflammatory cytokines, i.e. interleukin-1β (IL-1β), IL-6, and NO radicals. Indeed, METH induced expression of IL-1β mRNA in the rat brain [17]. Cadet and his colleagues reported that METH-induced neurotoxicity and gliosis were attenuated in IL-6 knockout mice [14], suggesting involvement of inflammatory cytokines in METH-induced neurotoxic cascade. Therefore, the present results suggest the possibility that ketoprofen might suppress production of inflammatory cytokines and NO, or suppress them indirectly through inhibition of microglia activation, with consequent amelioration of METH-induced neurotoxicity and microgliosis. Further study will be required to clarify mechanism of this protective effects.

I'd like to thank the contributors to this thread for doing such a wonderful job. As a smoker, I'd also like to add this study.

Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin

Karine Paraina, 1,
Céline Hapdeya, 1,
Estelle Rousseleta,
Véronique Marchandb,
Bernard Dumeryb,
Etienne C Hirscha,

Abstract

Epidemiological studies have found a negative association between cigarette smoking and Parkinson’s disease (PD). In order to analyze the putative neuroprotective effect of cigarette smoke and nicotine, one of its major constituents, we examined their effects in an animal model of PD provoked by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. Two groups of mice were chronically exposed to cigarette smoke (a low exposure subgroup and a high exposure subgroup; 5 exposures per day at 2-h intervals), two other groups received nicotine treatment (two doses tested 0.2 and 2 mg/kg, 5 injections i.p. per day at 2-h intervals) and one group placebo. On day 8 after the beginning of the treatment, 4 injections of MPTP hydrochloride (15 mg/kg, i.p., at 2-h intervals) or saline were administered to these animals. Nicotine and cotinine plasmatic concentration was quantified by the HPLC method, and degeneration of the nigrostriatal system was assessed by tyrosine hydroxylase (TH) immunohistochemistry. The loss of dopaminergic neurons induced by MPTP in the substantia nigra was significantly less severe in the chronic nicotine treatment groups (at 0.2 and 2 mg/kg) and the low exposure to cigarette smoke group than in the high exposure to cigarette smoke subgroup and the placebo treated subgroup. In contrast, no preservation of TH immunostaining of nerve terminals was observed in the striatum in any group. This suggests that nicotine and low exposure to cigarette smoke may have a neuroprotective effect on the dopaminergic nigrostriatal system by an as yet unknown mechanism.
http://www.sciencedirect.com/science/article/pii/S0006899303031950

Interesting, the smoke group likely is benefiting from MAO inhibition but the nicotine group I'm interested in. There is some research suggesting NAChR binding and presumably agonism by amphetamine being implicated in ROS generation, so I'd hazard a guess it may be due to receptor desensitization or upregulation of some sort of protective factor. Should be an interesting area to watch how the research develops.

I read somewhere that Methamphetamine at lower doses can actually be neuroprotective. After looking around I found this http://www.ncbi.nlm.nih.gov/pubmed/21635908

I'm curious just how low of a dose is considered neuroprotective, would anywhere from 10-25mgs be in this area?

I'm mainly curious because I've been reluctant on taking Desoxyn, but after hearing this I might get back into taking it every so often.

Assuming that study translates to humans, and there is a strong chance it doesn't given how different species are affected by amphetamines, it would be around 4-8mg for a 140lb or 70ish kg human. Its also worth noting that this is under stroke conditions, so its relevance to normal conditions might be minimal. Interesting nevertheless though, it points to downregulation of dopamine receptors being a possible contributing factor to the continued apoptosis seen days after the last dose given to rats.

 

[Dysphoric]

Assuming that study translates to humans, and there is a strong chance it doesn't given how different species are affected by amphetamines, it would be around 4-8mg for a 140lb or 70ish kg human. Its also worth noting that this is under stroke conditions, so its relevance to normal conditions might be minimal. Interesting nevertheless though, it points to downregulation of dopamine receptors being a possible contributing factor to the continued apoptosis seen days after the last dose given to rats.

well, assuming that it's around the 4-8 mgs. Would 15-25mg's make that much of a difference? I would think the neurotoxicity would be fairly benign at a dose a little over double the "neuroprotective" dose. Right?

 

[Epsilon Alpha]

well, assuming that it's around the 4-8 mgs. Would 15-25mg's make that much of a difference? I would think the neurotoxicity would be fairly benign at a dose a little over double the "neuroprotective" dose. Right?

Well assuming it applies to humans who aren't having strokes, using the roughly 16mg measure for humans showed mixed results in preventing the neurotoxic measures in intact mice. Some brain areas showed reduced toxicity due to the stroke and others showed more, at the lowest tested doses it was uniformly positive in the measured categories. This study isn't really applicable to human usage sorry to say, but who knows what further research in the topic turns out. But, benign? Defining benign is hard, but will it cause major issues before you're 50. Probably not, but talk that kind of thing over with a doctor, for all I know you're an obese diabetic with a heart problem or an Olympic athlete with ADHD. Its more of a quality of life thing though if you're not using it recreationally, and only you and your doctor can decide that.

Wish I could be more definitive, but the data doesn't give me anything I can reasonably apply to humans.

 

[atrollappears]

Well its a very multifaceted issue, particularly the toxicity that is observed days after last administration. But, this excerpt from the ketoprofen paper does a good job of explaining some of nitric oxide's acute effects.

IIRC, the behavioral effects of meth were attenuated or blocked in iNOS knockout mice... presumably meth need not generate reactive oxygen species (other than NO) to carry out its stimulant effects, so I'm guessing that the NO is created at some stage in its dopamine releasing action. But does this mean that the neurotoxicity of meth actually contributes to its behavioral effects, by generating additional NO? (Or is NO only related in that it's needs to be present for meth to work, but is not generated by meth's pure pharmacological action?)

Oh, by the way, I remember reading a study where tobacco smoke attenuated meth toxicity in mice.

 

[golden1]

Why exactly is NAC "really" bad? You seem to have just said that when many of the other substances listed also have possible side effects...

"The implications of these findings for long-term treatment with acetylcysteine have not yet been investigated. The dose used by Palmer and colleagues was dramatically higher than that used in humans;[24] nonetheless, positive effects on age-diminished control of respiration (the hypoxic ventilatory response) have been observed previously in human subjects at more moderate doses.[25]" from the wiki page on it that you linked..

However even after reading the abstract [25] I'm not sure if by "positive effects" which way they mean it. For example gasoline has a positive effect on a forest fire's growth, however many would consider that a negative.. if that helps anyone understand my confusion on the wording.

also "The dose used by Palmer and colleagues was dramatically higher than that used in humans," does mean anything? Where are the studies showing that it is really bad?

I'm asking because I've looked up all about the metabolite and it's adverse effects, however a low dose(300mg) when comparing the benefits to the negatives at much higher doses doesn't seem bad at all...
especially if you are taking it every so often and not daily(and I know you mentioned chronic dosing as worse, obviously, but I'm really curious why you labeled it so negatively mostly for my own knowledge)

 

[Epsilon Alpha]

Well I don't have any refs at the moment, but chronically NAC may downregulate the body's antioxidant defense mechanisms in a manner unique to its GSH mimicking properties. Not to mention I recall seeing a few studies showing it increased measures of sensitization chronically while being protective acutely. So is it safe every once in a while? Yeah. Is it safe every day, eating spoonfuls of the stuff? Not going to take my chances.
Part of it is also that glutathione seems to play a important role in INCREASING MDMA toxicity at higher doses and I don't want the science illiterate raver to come through this thread and think its a good idea to take MDMA or any of its RC counterparts with it.

More me just avoiding a small possible issue

 

[golden1]

Well I don't have any refs at the moment, but chronically NAC may downregulate the body's antioxidant defense mechanisms in a manner unique to its GSH mimicking properties. Not to mention I recall seeing a few studies showing it increased measures of sensitization chronically while being protective acutely. So is it safe every once in a while? Yeah. Is it safe every day, eating spoonfuls of the stuff? Not going to take my chances.
Part of it is also that glutathione seems to play a important role in INCREASING MDMA toxicity at higher doses and I don't want the science illiterate raver to come through this thread and think its a good idea to take MDMA or any of its RC counterparts with it.

More me just avoiding a small possible issue

ok I completely understand, safety first

I understand you do not recommend it with mdma and such(I've read same study(studies? probably, I forget) about the conjugations being more neurotoxic/a neurotoxic component. Do you remember if it applied to straight amphetamine? It does right? So me taking 300mg, say after the main effects of amphetamine wear off, is possibly(probably?) doing more harm than good? (my thoughts were that the extra gsh would have a net effect being positive due to all the other anti-oxidant effects+nac's anti-oxidant effects, and amphetamine use probably depletes gsh).

I realize you could easily have no idea(like me), since it's really all up in the air when looking at so many studies, but maybe you have an opinion on that? Maybe I should take the 300mg(every so often) only on days that I don't take amphetamine? That seems most reasonable right? I mean I also use ~500mg NA-R-ALA, ~1g alcar, 1g vitamin c(2-5 times spaced about an hour apart), vit E(not sure how much), 250mg magnesium, 500mg-1g cdp-choline, and fresh blueberry shakes(sooo good, also like the study that shows some constant % of diet containing blueberries raises BDNF levels(which I see as good, others might say messing with those are bad.. I disagree esp. if its caused by blueberries )). Oh and I smoke weed during lots of it, which I read seems to help, although it also sensitizes you(not quite sure on the meaning, but I assume thats why I feel much more euphoric smoking on amphetamine, that it is partly enhancing the action of the amphetamine.. not sure if that is an issue since I can just take less amphetamine and smoke and it feels like more, I don't think it's permanent sensitation and I'm not sure where I read that weed does this, but I think this thread or the last one. I also don't really understand sensitization, if someone wants to link to post explaining it better or explain for me the reason it's negative.. is it because only some parts you are sensitized to? so you have to take the same dose, yet some actions of the amphetamine are enhanced causing potentially more neurotoxicity? or some completely different reason?)

Thanks for making me remember about the gsh conjugates being neurotoxic, I think I let that slip or forgot it applied to straight amp(?) I probably would have come to the conclusion to take only on off days already(I don't use amp chronically, but enough I would like to protect my brain as much as possible haha.

If you see anything wrong with the other things I'm taking, please let me know :O I realize the na-r-ala dose is decently high, but it gives a rather fast subjective mind cleaning/fixing feeling at that dose compared to 100-400mg.

 

[Epsilon Alpha]

ok I completely understand, safety first
If you see anything wrong with the other things I'm taking, please let me know :O I realize the na-r-ala dose is decently high, but it gives a rather fast subjective mind cleaning/fixing feeling at that dose compared to 100-400mg.

By any chance are you bipolar? Insanely positive responses to antioxidants are something I've noted people mention online.
Like virtually all the positive responses I've heard for PQQ were from people with diagnosed or suspected (on their end) bipolar disease.

 

[golden1]

By any chance are you bipolar? Insanely positive responses to antioxidants are something I've noted people mention online.
Like virtually all the positive responses I've heard for PQQ were from people with diagnosed or suspected (on their end) bipolar disease.

I'm naturally an extremely happy person, with dips here and there(I'd consider it almost normal, except that weed might be helping to keep me so happy since If I don't smoke for a 1-2 days I start feeling depressed about anything possible(not all the time, but in bouts)...however I think that is just "withdrawal" from vape/smoking weed too much, since it will go away if I refrain getting high for like 4+ days).

I have much more reason to believe that I have some light form of ADD, mostly a lack of energy and inability to focus or do tasks that require too much thought(sometimes much worse than others and sometimes I have complete clarity).
I only call it ADD because it fits most, I have friend with much worse ADD symptoms, so I know I am not nearly full on ADD at all(his memory is also shit, way less attention span, and much more severe versions of my symptoms.. must be so shitty for him).

It's hard to tell if it's made worse by using drugs(long term) or if it's part of me(I suspect it's partly both because I remember the same symptoms in middleschool/highschool). Amphetamines make a huge difference, but then again for almost everyone they do. So does getting high, almost as effective, except energy wise.

I definitely have clarity that comes and goes, however if it's just due to a cycle such as not eating well when I feel fine and then eating extra well when I'm not etc, I don't know.


I'd also like to add that CDP-Choline makes a world of a difference to me, the onset feels like a small euphoric dopamine rush and the time after my wellbeing is greatly increased. When I took it daily I felt like I was cured of everything! I stopped when I ran out and my life got a bit more stressful to keep up on it, but I'm going to try it out again. I am wondering, wikipedia has abstract saying it increases specifically the d2 receptor(probably others d receptors too I'm guessing, but the test they used was only d2) density in rats with chronic dosing(also muscarinic acetylcholine receptor, I believe), I'm thinking either that or the effects on whatever else are the cause... only because I've taken alpha-gpc(no effect), choline citrate(no effect), choline bitartrate(extra sweating and fish smell all day LOL), and centrophenoxine(which gave me a hypomaniac-like mood lift and then sometimes depression the next day).

Anyway doesn't amphetamine internalize d2 receptors or something I read here? So cdp-choline could possibly help maybe through that mechanism?(my attempt to try to bring my post back to the topic lol)

 

[Dysphoric]

I'd also like to add that CDP-Choline makes a world of a difference to me, the onset feels like a small euphoric dopamine rush and the time after my wellbeing is greatly increased.

I'm interested in this now. Can anyone else vouch for this?

 

[MeDieViL]

Well I don't have any refs at the moment, but chronically NAC may downregulate the body's antioxidant defense mechanisms in a manner unique to its GSH mimicking properties. Not to mention I recall seeing a few studies showing it increased measures of sensitization chronically while being protective acutely. So is it safe every once in a while? Yeah. Is it safe every day, eating spoonfuls of the stuff? Not going to take my chances.
Part of it is also that glutathione seems to play a important role in INCREASING MDMA toxicity at higher doses and I don't want the science illiterate raver to come through this thread and think its a good idea to take MDMA or any of its RC counterparts with it.

More me just avoiding a small possible issue

Its a good idea to cycle nac with curcumin; curcumin in fact thrives on low glutathione and may work better after a nac cycle.

 

[MeDieViL]

Id say a racetam combined with a nmda antagonist is ideal in the scenario this thread is about this combination will help tolerance; potentiate amphetamine; offer neuroprotection and minimalise the comedown.

 

[Jabberwocky]

i've heard that methylphenidate has some neuroprotective elements to it, after doing quite a bit of research on the topic i am still puzzled as to how it does so. according to this study its binding on DAT receptors is what causes this to occur, but can kill the effects of an amphetamine high as excess dopamine is not pushed into the synapses. there is also another neuroprotective feature of mph is due to indirect use of VMAT-2. the study concludes that it is neuroprotective while being toxic at the same time. left me a little puzzled - as surely cocaine with also regulates dopamine is said to be highly neurotoxic and mph acts on the same principle just at a much lower level. the seizure threshold also increases vastly while using methylphenidate so i assume that that would always be a possibly especially if co-administered with amphetamines. receptors could be over stimulated using both together, it doesn't seem very promising but could be an alternative.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701286/

i've also heard that alprazolam is neuroprotective at low doses but for stress related illness. amphetamine increases gluthathione and catalytic activity in the brain under which alp reduces. i could be wrong so i wait to stand corrected of this.

personally what interests me vastly at the moment is selegine. although it is used for parkisons disease i think there is a world of potential to be gained from this drug especially when co-administered with l-dopa, both essentially cancelling out each others neurotoxic effects. as shown in parkisons suffers it can delay onset by up to 14 months but this shows that it is not a long term effective treatment.

as amphetamines can produce parkinson like features at higher doses or long term abuse i have been looking into the use of selegine too which is meant to provide neuroprotection through MAO-B inhibition. i have looked for further conclusive studies regarding the mechanism of action of selegine and no further studies have been taken to demonstrate its secondary course of action. as cigarettes also inhibit MAO-B i believe that this could also be a method of preventing neurotoxicity but the other chemicals involved in smoking a cigarette damage the neurones too giving a hit and miss situation. it also provides protection from 6-OHDA in vivo when used on animals, but possibly is not concurrent with humans. levo-dopa and Selegine has shown when used together to increase triatal superoxide levels or something along those lines too. it also increases the amount of n-acetylserotonin by the pineal gland although serotonin levels are not really of a concern regarding amphetamine abuse, it was shown to be a strong anti-oxidant which could stop amphetamine oxidising.

i'm also giving a brief guess as i haven't researched it but L-dopa is meant to stimulate dopamine response and help regain lost dopamine through the use of amphetamines. as amphetamines have been shown to provide oxidative stress amongst its users, it also seems that ,l-dopa has shown increase hydroxyl radicals as well so in a way it is also neuroprotective by increasing the levels of dopamine in the brain while being destructive at the same time hence why selegine or even possibly cigarettes could block these radicals due to the MAO abilities of it

thats my best bet on the subject of neuro protection regarding amp abuse, now where do i buy these compounds?

being a heavy amphetamine abuser myself, using l-tyrosine on days off seems to alleviate some of the psychological symptoms of not taking them along with a vitamin b6 complex. as it is a precursor to dopamine and in fact l-dopa it could provide some help in my opinion as the dopamine receptors can regenerate more quickly although i'm not really interested in l-tyrosine as i think amino acids are all a big gimic anyway. fish oils are meant to provide some sort of neuroprotectivity too but once again have done no research in the matter and that is fairly old.

from all concurrent research there has been no real major breakthrough in a drug which is neuroprotective fully that we have tested and know about to the present day which a bit upsetting. of course heading down using parkinson drugs to help with amphetamine damage is not really productive either.

Tianeptine is said to be an anti-depressant with neuroprotective features too, although it could be potentially deadly as NMDA receptors are opened at an extreme level leading to possible cell damage, but at a lower dosage have shown to be effective in increasing dopamine and boosting d2/d3 receptors as well. along with boosting serrortonin which will likely be lowered in the brain of a long term amphetamine user it also enhances the most damaged receptors in the brain of an amps user too.