Amphetamine Neurotoxicity and Tolerance Reduction/Prevention

[Epsilon Alpha]

I would be more than willing to contribute to this thread in more detail if people are interested. I have been taking D-amphetamine (ADHD treatment) now for the past 6 years and I would say that only in the last year have I worked out the things I need to do in terms of finding the right dose & how that relates to tolerance reduction and prevention.

I'd be up for hearing it

And continuing with the link dump.
http://www.sciencedirect.com/science/article/pii/S1471491408001354
http://www.sciencedirect.com/science/article/pii/S0896627311004338#sec1.2
http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03321.x/full

Also, switching to methylphenidate may actually help reverse amphetamine induced changes in DAT density just thought I'd throw that out there.

 

[AlexxRed]

I have certainly found supplements such as vitamins B, C, D & E in conjunction with magnesium & fish oil (in high doses) to be of great benefit. In the past when I had a supply of
piracetam I also used that, which seems to increase the effectiveness of amphetamine.

The MAO-B inhibitor L-Deprenyl is an interesting substance & some suggest it might help to repair damage caused by excess ampehatmine use. Word of warning DONT under any circumstance combine this with ampethamines or methylphenidate.

A previous thread has looked at using DXM to prevent tolerance...not sure how solid or practical that theory is....

 

[Epsilon Alpha]

Curcumin may reverse tolerance and epigenetic changes if used during periods of amphetamine abstinence! See the previous links I posted, you may have to use higher doses however.

 

[foliocb]

whats a high enough dose of curcumin?

 

[Epsilon Alpha]

whats a high enough dose of curcumin?

Anywhere between 1-8g/day assuming there's no special bioavailability modifications like piperine. Heads up its a wickedly strong anti-inflammatory, MAOI, and may cause gastric issues at that point. Read the thread below for more info on what to expect. Might be even lower depending on how your body metabolises it but I don't find that to be likely.

I'd say give it a 3-4 week trial if you really want to give it a chance to work. It also has a 3 day detectable period in the brain so be careful of that the next time you take amphetamine.

http://www.mindandmuscle.net/forum/neuroscience-nootropics/35183-curcumin-4.html

Valproate also shows promise in this as well, but be warned combining them with amphetamine may actually result in increased tolerance if the rat studies apply directly to humans.

 

[Fyasko.]

Oh i found out why i was freaking out that one day,
so on the curcumin bottle, the health facts say "turmeric root -- 395mg"

so i thought that it meant there was 395mg in it, then i see this lovely EXTREMLEY SMALL little tab on the top right corner of the label that says pull here, so i pull it and theres a whole nuther health facts sheet, and in big words it says "total curcumin -- 2500mg" so in all (on that day) i had abouttt 12.5g of curcumin lesson learned? read the fucking label front to back, side to side, make sure you've read everything 8)

 

[MeDieViL]

Since this thread is also about issues of amphetamine in general;

Its a very euphoric drug wich makes even ppl that need it addicted to it like me whenever i had this however there's a very promosing solution for this;
Add in a low dose risperdal, experiment take your prescribed dose and make sure you still get all therapeutic effects of that dose on your risperdal dose.

What happened now is that if you take a few extra addy's you wont get high you wont get any aditional energy and will still feel the therapeutic effects of amphetamine.

Youd probably keep trying to get a high out of it wich wont work but will lead to a waste of amp supply's however risperdal synergizes with amphetamine in activating the pfc wich over time makes you learn its futule to keep trying.
If im correct all nasty ap side effects shouldnt show up when combined with amphetamine.

I was skeptical about the learning but seeing improvement after a few days allready.

 

[Epsilon Alpha]

Ex Dubio

From Ex Dubio of Mind and Muscle

Looks like an interesting thread. Unfortunately, I'm pretty much swamped right now, so I won't have the free time to read through a beast like that for at least a few weeks.

I did read the first post, and I'll make a few quick comments.

1. Be warned that increasing VMAT2 -- e.g. by taking lithium -- is also going to blunt the effects of amphetamine. The amphetamine/VMAT2 interaction is complex and not fully elucidated, but there's reason to think that a significant part of amphetamine's mechanism of action is mediated through. In other words, while VMAT2 inhibition almost certain contributes to neurotoxicity, it may not be a good functional target.

2. Be aware that only methamphetamine is going to alter tryptophan hydroxylase expression, as methamphetamine -- but not amphetamine -- has significant affinity for the SERT. Also note that recent research has pointed to methamphetamine being intrinsically more neurotoxic than amphetamine.

3. Don't forget the trace amine receptor (TAAR). There are major species differences in TAAR expression, and TAARs seem somehow involved in amphetamine neurotoxicity in an important way. This may be one of the reasons that translating results between rodents and humans is so difficult.

4. I haven't had time to research it extensively, but nAChRs are likely involved more in amphetamine neurotoxicity than is commonly realized. Amphetamine has nontrivial activity at the alpha7 nAChR in particular, and blocking the alpha7 nAChR has somewhat fascinating effect on the results of amphetamine administration. This is a hugely important target in the coming decade.

5. Be careful in suggesting supplements to attenuate amphetamine neurotoxicity. For one, we don't know the extent to which neurotoxicity occurs in healthy humans at therapeutic dosing, so it may not even be necessary. But more importantly, compounds (e.g. NAC) that have been shown to attenuate neurotoxicity with acute administration (i.e. NAC administered acutely before amphetamine insult) may not do so with chronic administration, and may even paradoxically inhibit long-term resistance to oxidative stress.

6. Parkinson's disease prevention research is promising, but based on postmoterm studies in methamphetamine addicts, the region of the basal ganglia most severely impacted by [meth]amphetamine abuse is the caudate nucleus, whereas the region most severely affected in PD is the putamen. This may explain why [meth]amphetamine abuse leads to cognitive disturbance (controlled, in part, by the caudate) before it leads to motor disturbance (more controlled by the putamen). As a result, caution must be used in extrapolating these models.

7. Don't lose sight of the fact that nothing has been shown, in humans or even in primates, to prevent Parkinson's disease or to prevent chronic amphetamine neurotoxicity. We can speculate a great deal, but the species differences makes it very, very hard to be conclusive.

8. Finally, be careful with DAT transporter inhibitors. Methylphenidate, for example, prevents Parkinsonism and DA neurotoxicity in models of amphetamine neurotoxicity exclusively because it blocks amphetamine from getting into DA neurons and doing its job. Methylphenidate isn't really neuroprotective, it just essentially antagonizes the effects of amphetamine.

9. The notion of using curcumin is intriguing, and I've been researching curcumin for such purposes -- and others -- for a while now, but there's just not enough decent research on curcumin's ability to produce such results in vivo. There is some evidence for curcumin attenuating morphine tolerance, so it's possible, but the magnitude of effect is unclear. It's also complicated because curcumin is much more bioavailable in rodents than in humans. And then this is further complicated by the fact that high enough doses of curcumin actually induce oxidative stress and may be toxic in the long-term.

That's all I've got off the top of my head. Feel free to reproduce this (i.e. quote me) in the thread, if you want. I don't have a Bluelight username, so I figured I'd just reply in a PM.

If you have specific questions, I'm happy to answer -- or at least try to answer -- those.

-Ex

 

[Ex Dubio]

The MAO-B inhibitor L-Deprenyl is an interesting substance & some suggest it might help to repair damage caused by excess ampehatmine use. Word of warning DONT under any circumstance combine this with ampethamines or methylphenidate.

Indeed, deprenyl/selegiline is not appropriate for combination with amphetamine, but I'm not convinced it can "repair damage" either. To make sense of that, first you have to ask what damage amphetamine is causing. Long-term amphetamine administration induces short-term adaptations (e.g. VMAT2, DAT, D2, etc.) and epigenetic changes (e.g. CREB, etc.), and may also induce some mild (at therapeutic doses) neurotoxicity (i.e. DA neuronal death). Selegiline can't bring DA neurons back to life, so it's certainly not going to repair the worst-case scenario. Likewise, the short-term adaptations will revert to baseline on their own. And, on top of that, deprenyl has no evidence for inducing epigenic changes. So, in short, I don't see any mechanism by which it may repair "damage" done by amphetamine.

Do note that there is some evidence that selegiline can prevent amphetamine neurotoxicity, but this evidence is in rodents and only works if selegiline and amphetamine are taken together, which is a separate problem.

A previous thread has looked at using DXM to prevent tolerance...not sure how solid or practical that theory is....

There's a decent amount of theory -- at least in rodents -- and quite a bit of anecdotal evidence supporting the use of NMDA antagonists like DXM and memantine to do this. Practicality and safety are questionable, but efficacy seems pretty likely.

I'd be up for hearing it

And continuing with the link dump.
http://www.sciencedirect.com/science/article/pii/S1471491408001354
http://www.sciencedirect.com/science/article/pii/S0896627311004338#sec1.2
http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03321.x/full

Good references, but it should be noted that the processes traditionally seen in addiction are unlikely to occur to anywhere near the same extent in therapeutic use.

Also, switching to methylphenidate may actually help reverse amphetamine induced changes in DAT density just thought I'd throw that out there.

I doubt this is reversing anything epigenetic, though; it likely just speeds the return of DAT expression to baseline.

I wonder how much piracetam would help.

Can't say with the evidence that exists. There's not a lot of good evidence for piracetam being meaningfully neuroprotective in humans, at least outside of the rather exceptional cases of stroke and traumatic brain injury. The most we can really say about piracetam in halfway healthy humans is that it modestly improves memory.

Not sure if anyones brought up this study but here:
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-079X.2009.00741.x/full

just another reason to use melatonin

Melatonin is getting a lot of discussion around here, and with good reason, but there are some caveats. It has a significant negative effect on HPA axis activity (e.g. cortisol), and thus can potentially cause problems in those vulnerable to HPA dysfunction. It could conceivably also impair attention through similar mechanisms. Melatonin also has some mild antidopaminergic effects. It's neuroprotective, for sure, but do watch for the aforementioned side effects, and avoid melatonin like the plague if you have an autoimmune disease.

 

[Ex Dubio]

As far as preventing toxicity at +35mg or recreational doses that's a whole different ball game, and is something I'm working on. PQQ and low dose lithium have shown promise in some users who are taking higher doses, but there's plenty of other approaches we haven't touched on and personal chemistry to consider as well.

EA, where did you get the 35mg number for the divide between therapeutic and recreational? Seems like as decent a number as any, but I'm curious if you have hard evidence?

I have experimented with mixing PQQ in doses up to about 30mg with my usual dose of dextroamphetamine. I didn't notice any difference.

I am a skeptic by nature, so I would tend to be resistant to the placebo effect. In fact, if there was some barely-noticeable improvement, I would be more likely to dismiss it than to attribute it to the supplement. But I was hoping for a clearly-distinguishable difference, something that clearly justified taking the expensive supplements. I didn't find one.

What were you expecting from PQQ? Something with strong mitochondrial antioxidant properties like PQQ might be perceptible in terms of improving aerobic performance, but on the whole I'd expect it to have no perceivable effects. The point in taking it -- at least in the context of this thread -- would be to reduce the neurotoxicity of amphetamine, and that's not something you're going to be able to easily "feel".

so could some one sum up a nice neurotoxicty reduction stack ?

Only compounds I can think of off the top of my head with direct evidence (in rodents, at least) for a reduction of amphetamine neurotoxicity are CoQ10, selenium, melatonin, vitamin C, and perhaps magnesium.

There's indirect evidence for curcumin, fish oil, and a host of other antioxidants.

Was the curcumin effects noticeable? Also, did you take your L-Tyrosine on an empty stomach? I heard that if you take it with any protein in your stomach it pretty much makes it worthless since the Tyrosine will bind to the proteins and not get into your blood/brain.

It is necessary to take tyrosine on an empty stomach to obtain the desired effects, but it has nothing to do with tryosine binding to protein in your stomach. Instead, if consumed with other protein, the amino acids from that protein will compete with tyrosine for uptake into the brain, and thus an insufficient amount of the supplemental tyrosine will make it into the brain to be used in the production of catecholamines.

Do note, however, that rapid tolerance develops to tyrosine supplementation.

I've bought a magnesium supplement (I take Dexedrine IR). When's the best time to take them (morning/night or both?)? Take them with or without food? What's the best dose?

Probably doesn't matter when you take it or even whether you take it without food. It does make many sleepy, though, so night time is a good bet. 400mg is a standard dose.

Any of those drugs can cause anhedonia in very sensitive individuals, but MPH should be the least likely of them. MDMA toxicity is something I won't get into lest I turn this into a flame war, but suffice to say its pretty bitching at causing depression in a certain population.

Do keep in mind that all DA/NEergic drugs will cause a certain amount of anhedonia during acute withdrawal. That is, the "come-down" from MPH can certainly induce temporary anhedonia. That said, this anhedonia is due to temporary alterations in receptor expression and is not a long-term neurotoxic consequence.

 

[Ex Dubio]

Other than that the antibiotic I've been looking at is minocycline, but please unless it is already prescribed to you for a unrelated condition do not seek it out. Overuse of antibiotics is a big enough problem and I don't want to make it worse.

You have nothing to worry about. Minocycline, being a tetracycline, belongs to a class of drugs to which resistance is already well-developed to an extensive degree. Keep in mind, its cousins tetracycline and doxycycline have been used for years in treating acne and other long-term disorders. Basically, you can't do much harm by abusing this particular class of antibiotics, at least in terms of antibiotic resistance.

That said, minocycline looks promising for some disorders (e.g. MS), but its side effect profile is actually quite nasty, so that would be the more salient concern IMO.

would CoQ10 be worth the money? it looks fairly expensive.

Buy online, preferably in bulk. In the US at least, few places can beat Amazon or Swanson, particularly with the free shipping or "Subscribe and Save".

anyways i seem to be suffering from Anhedonia

Anhedonia is typically considered one of the cardinal symptoms of depression. As noted elsewhere, stimulants can certainly induce depression, so this may not be surprising. In such a circumstance, almost any standard antidepressant (SSRIs, MAOIs, St. John's Wort, TCAs, bupropion, etc.) should help. A stimulant-type antidepressant like bupropion (Wellbutrin) might be preferable.

I went ahead and bid on the ubiquinol anyway. There's nothing more annoying than having an experiment fail and not knowing whether it's because you took a shortcut and you need to redo it. I'd rather give it a full chance to work right off the bat. It's crying out for some scientifically-minded individual to do thorough comparisons between ubiquinol/ubiquinone, PQQ, Co-Q10, and PQQ + Co-Q10. Research materials can be hard to come by, I understand. The DEA probably would not be willing to provide access to samples of controlled substances for this kind of amateur research. If I had enough, I would be able to provide Dexedrine, but, unfortunately, my prescription is barely adequate as is. Does anyone want to send me samples of supplements, to augment my meager research budget? I promise to publish my results on this forum.

Actually, a lot can be said about ubiquinol vs. ubiquinone. The study (PMID: 17482886) covers this extensively. To make a long story short, ubiquinol and ubiquinone (CoQ10) have the same eventual fate when consumed, but the absorption of ubiquinol is significantly better than that of CoQ10. In fact, 100mg ubiquinol was roughly equivalent to 200-300mg CoQ10. As ubiquinol can be found online for roughly the same price, you end up getting a much better deal if you buy ubiquionol. But at the end of the day, the two compounds do the same thing.

Sadly, PQQ is not nearly so well researched.

 

[Ex Dubio]

The thing is, you can find low-quality studies that demonstrate just about anything. A few years ago, ginkgo biloba was a supposed cognitive enhancer, but this is what the wikipedia entry says now:

There still are several double-blind studies that show ginkgo does enhance cognition in elderly individuals. That particular issue is still up for debate, and there are a number of reasons -- including the use of different extracts -- that can explain why these studies might disagree.

By the time it's published in JAMA, the bullsh*t has been stripped away, and the facts are laid bare that it doesn't do whatever it was claimed to do based on small, flawed studies.

Hardly. JAMA fucks up plenty. Hell, they published the incredibly flawed results suggesting SSRIs were indistinguishable from placebo. It is wise to trust more respected journals more than less respected journals, but it's not as if JAMA, Nature, et al. never publish a flawed study.

This cycle has been repeated any number of times with various herbs and vitamins. Vitamin E was supposed to do a heap of wonderful things, and to my knowledge, none of them panned out. There are always low-quality studies supporting the supposed benefits. That's why they take the time to do the big expensive study that disproves it. You start to realize that bias is pervasive. People really want to believe that these supplements work, and it takes a well-designed study to change some people's minds. Some people, of course, go on believing in them even after they've been debunked.

A lot of these highly reported studies that "settle" a given issue are flawed themselves. The study that showed vitamin E increased heart disease risk was a poorly controlled epidemiological study that failed to take into account the fact that high-risk individuals were more likely to use vitamin E in the first place. Cross-sectional studies are always a weak form of evidence, and yet they are nonetheless published in major journals and reported in the news.

It often isn't an issue of bias, and is much more often an issue of methodology, differing extracts, poor study design, or similar factors. Yes, most compounds heralded as supplements probably do nothing in vivo, but there's a lot of nuance that a single "conclusive" study in any journal, including JAMA, is going to miss.

It looks like jlspartz was onto something with BDNF, it seems like it increases dopamine production which could explain its variable effects on cell metabolism and could have a positive effect on tyrosine hydroxylase. It could also keep your neurons a little bit further from apoptosis.

And for those of you who are curious, cucumin increases BDNF concentrations in the brain.

You have to be careful with BDNF. It is ostensibly involved in neuroprotection, but it's also involved in addition and tolerance. Increasing BDNF en masse is not necessarily a good thing at all. Perhaps more importantly. GDNF and NGF may be more important for DA neuron health than BDNF.

 

[Epsilon Alpha]

Hey, I'll try and make a big and dandy post summing up epigenetics and amphetamine when I have all the info I feel is appropriate, but further continuing the link dump:

http://www.ncbi.nlm.nih.gov/pubmed/20383415

PS: MeD if you're reading this congrats on switching from amphetamine to MPH+resperidone, I hope that proves sustainable for you and you can ween yourself off further polypharmacy.

 

[MeDieViL]

Im actually going back to amphetamine ritalin doesnt help my hyperactivity and i can no longer fully read full texts anymore just the interesting bits even tough it was as good for sa and motivation.

Weaning of polypharmacy wasnt something that was really an issue i never had issues with polypharmacy just with amphetamine addiction (wich risperdal will block too read the other thread) but i do beleive now that less agents or supplements is better for more effective results and avoiding interactions.

Didnt have problems with amp breaks much either, just completely overdoing when i start wich i no longer can on risperdal atleast on methylphenidate).
Thx for the head ups

 

[Epsilon Alpha]

Anybody care to detail the intracellular pathways the NMDAR antagonist approach acts on?
I really would be interested in seeing how and where it really works.

Thanks
-EA

 

[bben]

Anybody care to detail the intracellular pathways the NMDAR antagonist approach acts on?
I really would be interested in seeing how and where it really works.

Thanks
-EA

this can easily be found on google.

 

[Epsilon Alpha]

this can easily be found on google.

http://www.jneurosci.org/content/16/13/4231.short
Why won't you let me be lazy

 

[nj754]

What were you expecting from PQQ? Something with strong mitochondrial antioxidant properties like PQQ might be perceptible in terms of improving aerobic performance, but on the whole I'd expect it to have no perceivable effects. The point in taking it -- at least in the context of this thread -- would be to reduce the neurotoxicity of amphetamine, and that's not something you're going to be able to easily "feel".

vvViolet on this thread wrote up a report claiming that he felt a distinct difference from adding ubiquinol and PQQ to his amphetamine. That was what got my attention. I am not much interested in taking supplements just to reduce neurotoxicity, because the neurotoxicity itself is not well documented in humans, so you are piling speculation upon speculation by trying to defeat it. It's not worth the cost of the supplements.

There still are several double-blind studies that show ginkgo does enhance cognition in elderly individuals. That particular issue is still up for debate, and there are a number of reasons -- including the use of different extracts -- that can explain why these studies might disagree.

By the time it's published in JAMA, the bullsh*t has been stripped away, and the facts are laid bare that it doesn't do whatever it was claimed to do based on small, flawed studies.

Hardly. JAMA fucks up plenty. Hell, they published the incredibly flawed results suggesting SSRIs were indistinguishable from placebo. It is wise to trust more respected journals more than less respected journals, but it's not as if JAMA, Nature, et al. never publish a flawed study.

I am sure that's true. But, by and large, JAMA doesn't publish studies on dietary supplements unless they are of high quality. "It is wise to trust more respected journals more than less respected journals" -- that's all I'm trying to say.

This cycle has been repeated any number of times with various herbs and vitamins. Vitamin E was supposed to do a heap of wonderful things, and to my knowledge, none of them panned out. There are always low-quality studies supporting the supposed benefits. That's why they take the time to do the big expensive study that disproves it. You start to realize that bias is pervasive. People really want to believe that these supplements work, and it takes a well-designed study to change some people's minds. Some people, of course, go on believing in them even after they've been debunked.

A lot of these highly reported studies that "settle" a given issue are flawed themselves. The study that showed vitamin E increased heart disease risk was a poorly controlled epidemiological study that failed to take into account the fact that high-risk individuals were more likely to use vitamin E in the first place. Cross-sectional studies are always a weak form of evidence, and yet they are nonetheless published in major journals and reported in the news.

I think we pretty much agree. I don't put much stock in epidemiological-type studies, regardless of where they are published.

It often isn't an issue of bias, and is much more often an issue of methodology, differing extracts, poor study design, or similar factors. Yes, most compounds heralded as supplements probably do nothing in vivo, but there's a lot of nuance that a single "conclusive" study in any journal, including JAMA, is going to miss.

The bias is often in the interpretation. The numbers don't lie, but results of weak studies get blown out of proportion and used to support wished-for conclusions. The same kinds of errors are made over and over, so that it starts to become predictable.

Again, it's not so much where the study is published, but the fact that its a double-blind, placebo-controlled experiment that has been subjected to peer review.

 

[foliocb]

Im going to start taking 30mg of DXM twice a day for a week then possibly bump up to 120mg a day and see how it affects my adderal tolerance.

 

[foliocb]

I started taking 60mg of DXM a day to see if it helps with tolerance reduction. Should I stop taking Cucurmin since it's an MAOI? I dont want to fuck up my brain with this experiment... lol.