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Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

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Epsilon Alpha

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Link to previous thread:
http://www.bluelight.ru/vb/threads/...rotoxicity-and-Tolerance-Reduction-Prevention
The Basic Stack.
- ~250mg elemental magnesium at bed. Why: magnesium deficiency is extremely common and known to worsen neurotoxic measures in mouse models. May also help with bruxism (jaw clenching)
- ~1-5mg sublingual melatonin 3 hours before bed. Why: helps regulate sleep cycle, potent antioxidant, several neuroprotective mechanisms.
- Stay hydrated, preferably with high quality fruit juices (such as 100% blueberry) Why: do I really need to explain this?
- Eat a balanced diet rich in dark fruits and vegetables. Why: Why: do I really need to explain this? Make sure you eat period.
- Avoid overheating. Why: Elevated body temperature has been linked to increased neurotoxicity in mouse models
- Coenzyme Q10 at 100mg/day in a softgel or oil based formulation (preferably taken with food). Why: extremely long half life antioxidant, various beneficial effects on mitochondrial function.
- Avoid sleep deprivation. Why: your body needs sleep whether you want to or not.
- A good multivitamin, or at the very least vitamins A,C,E, and D as well as selenium at a significant portion of the RDA value. Malnutrition is a very real concern with amphetamine use,
-Low dose ASA ~81mg/day, anti-inflammatory drugs have shown to reduce neurotoxic measures in several models, also might give your cardiovascular system a break.
- Keep your dose as low as possible.

Now to sum up what we were talking about before:
Epigenetics:
There are various animal studies that suggest amphetamine produces a large portion of its sensitization via epigenetic changes primarily through CREB and histone deacetylase (HDAC) activity. However, if the mouse studies are to be applied to humans the picture becomes complicated. Co-administration of HDACI’s and amphetamine produces increased sensitization and conditioned place preference http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03321.x/full
Curcumin provides an interesting approach to this by inhibiting virtually every epigenetic mechanism under the sun, though the exact concentrations needed for significant inhibition of the various pathways in humans is still unknown at this point. CREB inhibition would stop the immediate-early response gene (IERG) activation and in turn long term epigenetic changes, while HDAC inhibition (a process downstream of CREB) would theoretically lead to an acute increase in sensitization and production of IERG proteins. Now during a “tolerance break” repeated HDACI application post amphetamine was shown to decrease sensitization which may be a relevant process in humans.
But, then there’s the possibility of histone acetyl transferase (HAT) playing a large role in the equation. Curcumin is a pretty bitching inhibitor of HAT, more so than HDAC in rats at least. This suggests that the potential negative effects of HDAC acutely on sensitization may not be an issue. http://www.ncbi.nlm.nih.gov/pubmed/20383415
But, going back to the IERG’s it appears that they also play a role in the NMDA antagonist mechanism of action via CREB http://www.jneurosci.org/content/16/13/4231.short. And, curcumin appears to have a effect on NMDA calcium influx too http://www.ncbi.nlm.nih.gov/pubmed/20015232.
So to sum it all up: curcumin is kind of like the sawn off shotgun of epigenetic modulators, showing promise on several fronts but with its 9/21 positive response rate we’d need better controlled anecdotal or actual clinical trials to make more sense out of it. Also, there may be glaring species differences with the various proteins curcumin binds between humans and rats/mice that I’m too lazy to check out (hint hint). Also, don’t be afraid of trialling more selective inhibitors of epigenetic mechanisms as long as you’re smart and methodical about it.
http://www.ncbi.nlm.nih.gov/pubmed/21466474

Sensitization vs Tolerance.
This is a particularly interesting issue, as it involves both epigenetics and the strengthening/weakening of a ton of pathways in the brain. I’ll fully admit that I’m not that well versed on the topic (somebody grab Ex Dubio :p) but it plays into the idea that a portion of "tolerance" may be specific pathways in the brain adapting to amphetamine use.

A very interesting study came out a couple weeks ago, and though it's hard to say how relevant the implications are to humans, the study nonetheless puts forth some very intriguing ideas.

First, a quick refresher. Sensitization is a rather complex process that occurs when rodents are given [strongly] DAergic drugs or, as they are commonly known, "drugs of abuse". Sensitization refers to the phenomenon in which responding to a drug (measured typically by means of locomotor activity) is increased with repeated administration. For example, locomotor responding to amphetamine tends to increase -- not decrease, as would be expected with tolerance -- when amphetamine is given repeatedly, assuming a few technical criteria are met. What is particularly important, though, is that sensitization persists after months -- and even years -- of abstinence from a given drug.

Now, the catch is that we don't really even know if sensitization occurs in humans, but sensitization is nonetheless often taken as a model for the maladaptive neurological changes that occur in addiction. (Note that it may be that sensitization and tolerance happen simultaneously, but are expressed differently, in humans. It's not clear to me how well we can judge tolerance (i.e. to rewarding effects) in rodents.) So, assuming that sensitization -- or something like it -- occurs in humans, being able to quickly "break" sensitization -- which seems to otherwise persist indefinitely -- could completely change the landscape of addiction treatment. If fact, if the link between sensitization and addiction is correct, then "breaking" sensitization could be a rapid "cure" for addiction. Note that it is quite possible that this is precisely what compounds like ibogaine do.

As if that weren't enough, I have a pet theory that sensitization may be related to the development of motor complications like bruxism with extended use of amphetamine, cocaine, MDMA, and similar drugs. As many an MDMA user can attest, being able to prevent the bruxism that often accompanies frequent MDMA use would be a major boon.

And "breaking" sensitization is precisely what these researchers claim they have accomplished, with a rather unorthodox combination of a D1/D2 agonist (pergolide) and either a 5-HT3 antagonist (ondansetron) or a 5-HT2A/2C antagonist (ketanserin). Though the protocol might be tricky to adapt to humans, and suitable drugs might be hard to obtain, if it can truly reverse what we believe to be the manifestations of sensitization in humans, it would be game-changing. So without further ado, I present the study:

Behav Brain Res. 2011 Sep 30;223(1):227-32. Epub 2011 May 7.
Reversal of long-term methamphetamine sensitization by combination of pergolide with ondansetron or ketanserin, but not mirtazapine.

Bhatia KS, Szabo ST, Fowler JC, Wetsel WC, Lee TH.
Source

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

Psychostimulant abuse represents a psychiatric disorder and societal concern that has been largely unamenable to therapeutic interventions. We have previously demonstrated that the 5-HT₃ antagonist ondansetron or non-selective 5-HT(₂A/₂C) antagonist ketanserin administered 3.5 h following daily pergolide, a non-selective DA agonist, reverses previously established cocaine sensitization. The present study was conducted to evaluate whether the same treatments or delayed pairing of pergolide with the antidepressant mirtazapine can also reverse consolidated methamphetamine (METH) behavioral sensitization. Sprague-Dawley rats received METH infusion via osmotic minipumps (25 mg/kg/day, s.c.) for 7 days, with accompanying daily injections of escalating METH doses (0-6 mg/kg, s.c.). This regimen takes into account the faster elimination of METH in rats, and is designed to replicate plasma METH concentrations with superimposed peak drug levels as observed during METH binging episodes in humans. Following a 7-day METH withdrawal, ondansetron (0.2 mg/kg, s.c.), ketanserin (1.0 mg/kg, s.c.), or mirtazapine (10mg/kg, i.p.) was administered 3.5 h after pergolide injections (0.1 mg/kg, s.c., qd) for 7 days. Behavioral sensitization as a model of METH abuse was assessed 14 days after the combination treatment cessation (i.e., day 28 of METH withdrawal) through an acute challenge with METH (0.5 mg/kg, i.p.). Pergolide combined with ondansetron or ketanserin reversed METH behavioral sensitization, but pergolide-mirtazapine combination was ineffective. The role of reactivation of addiction "circuit" by a non-selective DA agonist, and subsequent reconsolidation blockade through 5-HT₃ or 5-HT₂ antagonism in reversal of METH sensitization and treatment of METH addiction is discussed.
Copyright © 2011 Elsevier B.V. All rights reserved.

PMID:21571009 [PubMed - indexed for MEDLINE]
PMCID: PMC3113440 [Available on 2012/9/30]
http://www.mindandmuscle.net/forum/neuroscience-nootropics/40750-sensitization-breakthrough-2.html

To discuss: TAAR, MGluR, NAChR, 5HT3R, long term potentiation, and further mechanism of cell death/dysfunction.
 
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Good to see you back, Epsilon Alpha. Your contributions are a huge asset to ADA.

A few points:
1. I believe we talked about about magnesium's effect on neurotoxicity in a thread a while back, using MPTP as a crude model for amphetamine. The studies I posted mostly leaned toward (normal amounts of) magnesium being protective against neurotoxicity, but there was still that one study which seemed to indicate a pretty big exacerbation of MPTP toxicity in a not-too-ridiculous dosage of magnesium (and there was the matter of another study referenced in that study which supposedly claimed that magnesium exacerbated l-amph neurotoxicity, though I don't believe we ever accessed that study and looked at the amounts used). So, did you find anything new?
2. I would recommend acetyl-L-carnitine and (if you have a buffering agent) alpha lipoic acid as supplements for amphetamine users as well. ALC has been shown to protect against amphetamine (and I think MDMA too) neurotoxicity, and has also been shown to substantially improve cognitive function (in a perhaps biased study) when administered in conjunction with ALA, which is also a potent antioxidant.
3. As far as effects outside the brain go, some studies say ASA isn't really that effective for helping your heart, and can increase the risk of hemorrhagic stroke and ulcers. It's also unclear how the vasoconstriction caused by aspirin in some areas would combine with that already caused by amphetamine. Just some things to bear in mind if you're starting to take aspirin daily.

I'll give this the in-depth reading it deserves later, but for now I've got some work to do.
 
Careful messing with epigenetics---it may be the brain's defense mechanism. In one study rats exposed to amph in adolescence were resistant to neurotoxicity in adulthood due to epigenetic changes.
 
...In one study rats exposed to amph in adolescence were resistant to neurotoxicity in adulthood due to epigenetic changes.

Perhaps why I myself am so overly prone to amphetamine psychosis; I never touched it until nearly 30 years old.
 
Good to see you back, Epsilon Alpha. Your contributions are a huge asset to ADA.

A few points:
1. I believe we talked about about magnesium's effect on neurotoxicity in a thread a while back, using MPTP as a crude model for amphetamine. The studies I posted mostly leaned toward (normal amounts of) magnesium being protective against neurotoxicity, but there was still that one study which seemed to indicate a pretty big exacerbation of MPTP toxicity in a not-too-ridiculous dosage of magnesium (and there was the matter of another study referenced in that study which supposedly claimed that magnesium exacerbated l-amph neurotoxicity, though I don't believe we ever accessed that study and looked at the amounts used). So, did you find anything new?
Well massive doses of magnesium will do far more than just mess up your response to amphetamine, its a inverse U shaped curve with NMDA activity and magnesium concentration. Magnesium is probably only a good idea to supplement if you have a deficiency in it (and chances are you do).

2. I would recommend acetyl-L-carnitine and (if you have a buffering agent) alpha lipoic acid as supplements for amphetamine users as well. ALC has been shown to protect against amphetamine (and I think MDMA too) neurotoxicity, and has also been shown to substantially improve cognitive function (in a perhaps biased study) when administered in conjunction with ALA, which is also a potent antioxidant.
Interesting, I'd like to see some links for that. CoQ10 is my staple just because its stupidly safe and has a ~31 hour half life.

3. As far as effects outside the brain go, some studies say ASA isn't really that effective for helping your heart, and can increase the risk of hemorrhagic stroke and ulcers. It's also unclear how the vasoconstriction caused by aspirin in some areas would combine with that already caused by amphetamine. Just some things to bear in mind if you're starting to take aspirin daily.
It may just be COX inhibition in general that causes the sparing of DA neurons in the studies I've been reading, but ASA seems to have a favorable risk/benefit ratio to me. But as far as vasodilators go, Ginkgo has some promise in amphetamine useage but I haven't fully evaluated its safety.
http://www.nature.com/npp/journal/v25/n4/full/1395696a.html


blueberries
Fucking this :D

But, as far as the epigenome goes we're only now beginning to understand it. However, a curry and speed binge hasn't killed anyone yet (dispite 12.5g of curcumin and 90mg D-AMP...). But, I've seen a lot of evidence suggesting that things like deltaFosB and genome wide methylation are both protective and harmful at the same time.

Here's a really interesting paper on sensitization in humans from Nature.
http://www.nature.com/npp/journal/v25/n4/full/1395696a.html

Buuuuut, sensitization has way way too many links to bipolar disease and schizophrenia for my liking. Granted it may also be involved in some of the benefits seen in long term stimulant treatment of ADHD.
D1 antagonists in monkeys seem to reverse it http://www.sciencedirect.com/science/article/pii/S0091305710001899
Amp sensitization looks a lot like schizophrenia http://archpsyc.ama-assn.org/cgi/content/abstract/68/6/545
Looks to me like ADHD could predispose someone to sensitization http://archpsyc.ama-assn.org/cgi/content/abstract/63/12/1386
And a little info on the sensitization-bipolar link. http://www.sciencedirect.com/science/article/pii/S0166432809005841

I'm beginning to think that by looking into schizophrenia and bipolar/epilepsy we can begin to find some significant findings for all these conditions.
 
Yeah, did you ever figure out how high concentrations of Mg act as a Ca agonist? Or locate any studies that used amphetamine with reasonable concentrations of magnesium?

And here's some stuff on acetyl-L-carnitine, looks very promising IMO. In the MDMA study, note the essentially complete lack of 5-HT depletion in the ALC + MDMA group.
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2002.tb04164.x/abstract
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2003.tb07530.x/abstract
http://www.sciencedirect.com/science/article/pii/S0306452208015947
Couldn't find anything on alpha lipoic acid for amphetamine, but here's a study where it also fully prevents MDMA induced 5-HT depletion.
http://www.ncbi.nlm.nih.gov/pubmed/10619665
And a study of the combination in age-associated memory impairment:
http://juvenon.com/pdfs/juvenon_memory.pdf


Edit: That paper on sensitization is, as you say, interesting. Funny that drug liking and the rating of "euphoria" don't go hand in hand. How much is known about the neurochemical basis for sensitization? Between that odd relationship of drug liking to euphoria (mGluR5 antagonists, anyone?) and the link to schizophrenia/bipolar, it screams glutamate to me...
 
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Well at normal levels magnesium prevents excessive activation of NMDA, no big surprises there.
http://www.nature.com/nature/journal/v307/n5950/abs/307462a0.html

However, higher doses may antagonize the actions of endogenous NMDA channel blockers. IIRC at really high doses it also increases NE efflux which would explain the l-amphetamine bit. http://www.ncbi.nlm.nih.gov/pubmed/22261381

Your study showing increased stereotyping in response to l-amp and apomorphine, is in the discussion linked to increased cAMP production and NE/DA binding, and the doses are pretty high. http://www.sciencedirect.com/science/article/pii/0091305790901207

So it all kind of comes back to the inverted U curve with magnesium as far as I can tell. Stuff will bind to literally anything given high enough concentrations, much like lead.
 
Ah okay. The MPTP study that led me to that l-amp study said that the latter study showed an increase in neurotoxicity; did they measure DA/DA metabolite content or did they mean something different by "neurotoxicity"?
 
Also, why do we want to block sensitization anyway? It seems like a positive to me, I want to experience increased "euphoria" and "vigor" from amphetamine without feeling as much as though the drug has rewarded me :p
 
How would this apply to methylphenidate's neurotoxicity or tolerance? What doses would causes mild to severe changes by low to high doses of methylphenidate, I would think that they the synapses would be spread further apart and a lot less because of down regulation. Is this down regulation permanent if taken during your childhood and adolescence's developing brain, and if it's not just down regulation that is in effect with methylphenidate, what other things come into play that would create long-term changes?
 
Eplison Alpha and atrollappears, what do you two think of of the possibility of an anti-oxidant stack turning pro-oxidant in presence of MDMA/METH? Also, are you aware daily anti-oxidants will likely DOWNREGULATE endogenous production of the brain's own anti-oxidants? This means if one day you skip those anti-oxidants and something in your brain causes damage that requires internal protection, we're fucked. Selegiline I believe up-regulates said production, one reason why it's so interesting.
 
Eplison Alpha and atrollappears, what do you two think of of the possibility of an anti-oxidant stack turning pro-oxidant in presence of MDMA/METH?

Melatonin has been shown to turn pro-oxidant in the presence of chronic moderate to large doses of methamphetamine. Not sure if this is specifically something you were addressing, but, FWIW.

~ vaya
 
Now this is the kind of discussion I'm talkin' about!

Well my take on the antioxidant supplementation bit is that at the point when your body's endogenous defense mechanism are overloaded, at the point when oxidative stress is great enough to begin with to turn things like CoQ10 pro-oxidant I feel that having them mop up the significant amount of ROS and RNS before they themselves become pro-oxidant produces a net benefit. There's also several studies showing excessive oxidative stress in amphetamine users on the greater scale which I'd take as evidence for the use of antioxidants.

http://onlinelibrary.wiley.com/doi/10.1111/j.1369-1600.2009.00176.x/full
Also, by no means do I expect oxidative stress to be the sole mechanism through which amphetamine exerts its toxic effects and as such antioxidants may only provide partial protection.
http://www.sciencedirect.com/science/article/pii/S0892036209002001

Melatonin has been shown to turn pro-oxidant in the presence of chronic moderate to large doses of methamphetamine. Not sure if this is specifically something you were addressing, but, FWIW.

~ vaya
I'd be very interested in seeing that study if you could bring it up.

I'd also be up for seeing some studies showing selegiline upregulates your brains protective systems if you can dig them up.
 
How would this apply to methylphenidate's neurotoxicity

From my understanding methylphenidate, being a DRI unlike methamphetamine, is neuroprotective and not neurotoxic. Tolerance & down-regulation are different issues.
 
I'd also be up for seeing some studies showing selegiline upregulates your brains protective systems if you can dig them up.

But that doesn't address the down-regulation supplements cause, and also how the brain quickly and effectively builds a defense against even the most potent neurotoxins, at least at recreational doses, we aren't IV'ing MPTP here, and it does it on it's own.

http://www.ncbi.nlm.nih.gov/pubmed/15959853
 
From my understanding methylphenidate, being a DRI unlike methamphetamine, is neuroprotective and not neurotoxic. Tolerance & down-regulation are different issues.

With that being said, are there no danger's associated with prolonged therapeutic high doses of Methylphenidate from childhood to adolescents and onwards? Also, if your brain is used to having this for prolonged periods during development, when it's stopped, would you not be left blunted in terms of development of the brain? What I'm trying to say is, would someone be cognitively better or worst from this treatment, or would it predispose one to some other mental illness?
 
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