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Amphetamine Neurotoxicity and Tolerance Reduction/Prevention III

Joker11789 said:
I have to ask...I read threw all of this and it's obviously informative but I still am unsure of how to get the most out of my adderall 20mg XR ...

let's say tolerance isn't the issue etc etc ..

besides sodium bi. And empty stomach , alkaline diet? ...anything else and only hydrate with water avoiding acidic acid/critic/etc ?
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You could try sulbutiamine a priori.
 
Joker11789 said:
Thnx ..what's that lol ? I'm not as advanced with all this as you all seem to be .
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Thiamine-sulfur-thiamine or B1-S-B1, vitamine form that easily crosses blood brain barrier. Enhances arousal and decreases dopamine release which increase dopamine reseptor density which could enhance the effects of amph. Results will wary between people and state of mind, if already sufficiently aroused effect could be neglible.
 
HoChiMin said:
But your suggestion makes it a posteriori
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I just tried sulbutiamine a priori in like 30 thought experiments though. . . :p

coccie said:
Enhances arousal and decreases dopamine release which increase dopamine reseptor density which could enhance the effects of amph.
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I don't think that the magnitude of these mechanisms has been assessed so as to demonstrate definitively whether they are behaviorally relevant.

ebola
 
ebola? said:
I just tried sulbutiamine a priori in like 30 thought experiments though. . . :p



I don't think that the magnitude of these mechanisms has been assessed so as to demonstrate definitively whether they are behaviorally relevant.

ebola
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The magnitude of the effects seems to be very dependent on brainchemistry, combined it with 4-fma with great effect, now on ssri and noticed no effect.

Maybe grapefruit could extend the elimination half life?
 
coccie said:
Thiamine-sulfur-thiamine or B1-S-B1, vitamine form that easily crosses blood brain barrier. Enhances arousal and decreases dopamine release which increase dopamine reseptor density which could enhance the effects of amph. Results will wary between people and state of mind, if already sufficiently aroused effect could be neglible.
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Thanx again .
 
L lysine depletes nitric oxide as it saturates the arginine transporter or whatever it was called, as nitric oxide is behind tolerance and withdrawal of many drugs i hypothise its a natural alternative to memantine for tolerance.

Hopefull some guys will try it and report back.
 
Added info.

Hey guys I've only I think posted once previously (maybe twice) so many of you don't know me but I take Dex for ADD (had it since a child) but haven't taken it long term apart from recently (2 years with weekend breaks) problem is here in VIC Australia they have a limit on one twice a day of 5mg pure dex. I recently came across an article on damage done to the brain on amphetamines which got me concerned but everything seemed to link to Methamphetamine as opposed to Dexamphetamine (quick wiki search shows Meth is a neurotoxin vs Dex is not) but anyways, just wanted to safe guard myself and others have talked about the issue anyway.

Found many forums talking about it and they take certain things for it, even you guys I think compiled a list of what would be good things to take cause it either does or "should" help.


Came across this from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670101/

As noted above, a genotype that codes for lower density of dopamine D2 receptors (compared to a parallel functional polymorphism), protects against amphetamine-induced psychosis 198. Treatment with either lithium or valproate reportedly protect against dextroamphetamine-induced alterations of brain choline concentration in patients with bipolar disorder 216. Recent studies in animals have produced evidence for neuroprotection against amphetamine-mediated toxicity by several substances, including nomifensine 217, methyllycaconitine 218, coenzyme Q10 219, baicalein 220 and melatonin 221. In addition, impairment of learned place preference consolidation by amphetamine-induced neurotoxicity was ameliorated by administration of a glutathione precursor 222.

Seems to be some pretty solid information. Now apart from Nomifensine and Methyllycaconitine the rest seem be ok to get. Baicalein is a substance found in Skullcap (Chinese version mostly from what I've seen although some Americans ones might, Chinese seem to have the most research done to it) although there seems to be rumors or cases of liver failure whilst on it, but it has been in combination with other substances so they are not 100% sure but still believe it might be skullcap. I've been taking some but I take Taurine (1000mg a day, thinking about upping it to twice a day before my dex doses as they are between meals) to protect the liver (milk thistle also can do this though but Taurine has many other benefits also) and I also take solid whole food organic multi vitamin (whole food so it gets absorbed the best) and Q10 and melatonin, not to mention krill oils for EPA and DHA.
 
MrSpeedyG said:
I fail to see how meth can be neurotoxic yet regular amphetamine isn't?
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Regular? Actually there is no "regular" amphetamine, amphetamine is a parent class of two substances hence amphetamine is a stimulant of the phenethylamine class. From there, there are two substances which we actually consume levoamphetamine and dextroamphetamine (or dexamphetamine, depending on the country)

Or to take a quote from Wiki : Amphetamine properly refers to the racemicfree base, or equal parts of the enantiomers levoamphetamine and dextroamphetamine in their pure amine forms.


If you are referring to dex as the regular which is incorrect but ok, the body does process them very differently hence why meth was quickly outlawed for its toxicity.

I have actually noticed because you prompted me to look at the wiki again they have changed it and noticed there was an update.... it now reads :

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.[73] There is no evidence that amphetamine is directly neurotoxic in humans.[74][75] High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[12][76][77]

As opposed to before read along the lines of "Unlike Methamphetamine, Dextroamphetamine is not a neurotoxin"

Seems like now it is still not directly Neurotoxic but does damage as I've read you guys (and other people in other forums) discussing.

Either way as I mentioned I was taking precautions as per my post taking supplements. Whether they are doing anything is another matter, as most of the stuff I've read, every time seems to be about methamphetamine.


******Edit

Found the other post I was looking for.....


Neurotoxicity

Unlike amphetamine, methamphetamine is directly neurotoxic to dopamine neurons.[25] Moreover, methamphetamine abuse is associated with an increased risk of Parkinson's disease due to excessive pre-synaptic dopamine autoxidation, a mechanism of neurotoxicity.[26][27][28][29] Similar to the neurotoxic effects on the dopamine system, methamphetamine can also result in neurotoxicity to serotonin neurons.[30] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.[31] As a result of methamphetamine-induced neurotoxicity to dopamine neurons, chronic use may also lead to post acute withdrawals which persist beyond the withdrawal period for months, and even up to a year.[26]


Yeah as above the normal "withdrawal" period for dexamphetamine is 3 - 4 weeks, which is similar to my personal experiences, less if I use supplements.

Would also like to add it seems there has been research done to reverse existing damage done by amphetamines.

Taken from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769923/

Recent animal studies have produced evidence for neuroprotection against amphetamine-mediated toxicity by several substances, including nomifensine100, methyllycaconitine101, coenzyme Q10102, baicalein103 and melatonin104. Impairment of learned place preference consolidation by amphetamine-induced neurotoxicity was ameliorated by administration of a glutathione precursor105.


Glutathione is comprised of three amino acids (the precursor as mentioned above that ameliorated toxicity): cysteine, glutamate, and glycine.
Glutathione is sometimes confused with glutamine and glutamate due to the similarity in names. Although all three molecules are related, they are different in composition and function. When you are healthy, the three are balanced and do a delicate dance within your body.
In a nutshell, this is the difference between the three:

  1. Glutamine: Your body’s most abundant amino acid, made in your brain from glutamate; has a major role in various anti-injury processes and muscle repair; a precursor to glutathione.
  2. Glutathione (two types, GSH and GSSG): The “master antioxidant”—most powerful antioxidant in your body, present in every cell. Protects cells, and especially important for liver health; breaks down into free glutamate.
  3. Glutamate (aka glutamic acid or L-glutamate): Monopeptide amino acid neurotransmitter in your brain—required for synaptic activity. You don’t want too much of it—it’s an excitotoxin. (See also monosodium glutamate, or MSG)
Glutathione is different from other antioxidants in that it is intracellular. It has the unique ability of maximizing the activity of all the other antioxidants, including vitamins C and E, CoQ10, alpha lipoic acid, and the fresh veggies and fruits you (hopefully) eat every day. It removes toxins from your cells and protects you from the damaging effects of radiation, chemicals, and environmental pollutants.

Ironically, glutathione supplements may actually interfere with your body’s own glutathione production so if you are going to go the supplement route like I have just done order I'd recommend taking a form of cysteine known as N-acetyl-cysteine (NAC), but I would advise against using this supplement if you still have mercury amalgam fillings because it could interfere with detoxification of the mercury.

If you want to go the natural non supplement route :



  • The overall top food for maximizing your glutathione is high quality whey protein. It must be cold pressed whey protein derived from grass fed cows, and free of hormones, chemicals and sugar.
    Quality whey providesall the key amino acids for glutathione production (cysteine, glycine and glutamate) and contains a unique cysteine residue (glutamylcysteine) that is highly bioactive in its affinity for converting to glutathione.

    Glutamylcysteine is a bonded cysteine molecule (cysteine plus glutamate) that naturally occurs in Bovine Serum Albumin – a fragile immune component of the whey. This unique cysteine is exclusive to whey and rarely appears in other protein foods – which makes whey protein the best glutathione-promoting food source.

    Furthermore, whey provides critical co-factors, immunoglobulins, lactoferrin and alpha Lactalbumin (also a great source of cysteine), which together help create the right metabolic environment for high glutathione activity.
  • Raw milk products, raw eggs and meat: Glutathione occurs in the highest levels in fresh, uncooked meats and raw milk,but is almost entirely absent in pasteurized dairy products.
  • Fresh fruits and vegetables provide excellent glutathione, but once cooked, values become negligible. Spinach, potatoes, asparagus, avocado, squash, okra, cauliflower, broccoli, walnuts, garlic and tomatoes have the highest glutathione per serving.
  • The herb milk thistle is an excellent source of the antioxidant compound silymarin, which may help to prevent glutathione depletion in the liver. Glutathione is crucial in the liver for detoxification and can become depleted from acetaminophen (Tylenol), alcohol consumption, and general toxic overload.
  • Curcumin may also be useful for increasing glutathione levels.



Also to help curb tolerance I've seen around suggested (natural route) magnesium. Couple of problems are, bioavailability and the ability to cross the blood brain barrier. I take a combination of NOW Malate Magnesium which is helpful for production of energy (great for when you are coming down off dex) and magnesium threonate for its ability to cross the blood brain barrier. Most people I've seen that take magnesium and report it not working are taking the wrong type and or with calcium (which makes it useless for what we are trying to achieve)
 
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On the melatonin topic The thread above (from what I can gather from the abstract) shows that melatonin control was used and ethanol dose dependent administration reduced neurotox. But when melatonin and ethanol were combined they were not much more effective and Melatonin itself was completely ineffective.

Regardless one interesting aspect to neurotoxin prevention is usage of amino acids + guy microbe producing agents. Many amino acids undergo transmutation in the body as a method of producing energy during the glucose alanine cycle etc however many become excreted as free amino acids to the gut.

From the gut these amino acids are then turned into their carbon skeletons ala whatever removal of the amine group by BACTERIA etc I can't post links for some reason but here is the quote.

Google hmbd Indole 3 propionic acid

"Indole-3-propionate (IPA), a deamination product of tryptophan formed by symbiotic bacteria in the gastrointestinal tract of mammals and birds. 3-Indolepropionic acid has been shown to prevent oxidative stress and death of primary neurons and neuroblastoma cells exposed to the amyloid beta-protein in the form of amyloid fibrils, one of the most prominent neuropathologic features of Alzheimer's disease. 3-Indolepropionic acid also shows a strong level of neuroprotection in two other paradigms of oxidative stress."

So this is the one major product of 5htp usage especially preloading stacks...

The carbon skeleton of 5htp is nonpolar enough to enter the brain and it will enter ala a negative ion amino acid transporter but won't be readily removed.

So specific amino acids and gut microbes?
 
gearjammer said:
Sorry to jump in here but should I booty bump Selegiline?
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Well, it has a horrible swallowed bioavailability. 8 times as strong when held in the mouth:

Clarke A, et al, 2003, A new formulation of selegiline: improved bioavailabiliy and selectivity for MAO-B inhibition. download
 
Thanks, Red. I started on a course of l-deprenyl yesterday morning. 5mg orally yesterday and 10mg orally today. Noticed improvements in cognition, impulse control and concentration (duration of sustained concentration in particular). I will try the sublingual ROA and let you know if I notice any difference :) Contraindicated for amphetamine, I know, but would sublingual absorption and the marked decrease in amphetamine metabolites that go with it make concurrent use of dexamphetamine safer?
 
MAO-B inhibitors don't interact that strongly with amphetamine. MAO-B doesn't metabolize amphetamine, but it does metabolize its naturally occurring analogs in the body, so it might lower the dose you'd need to acquire its therapeutic effect. Not going to comment on recreational use effects.
 
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MrSpeedyG said:
I fail to see how meth can be neurotoxic yet regular amphetamine isn't?
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The difference between phenethylamine (a neurotransmitter created within brain monoaminergic neurons which strongly modulates the synaptic transmission of dopamine, norepinephrine, histamine, and serotonin) and amphetamine is exactly 1 methyl group. The difference between amphetamine and methamphetamine is 1 methyl group.

If 1 methyl group can't affect a chemical's cytotoxic properties, then your brain makes a direct neurotoxin (this follows from a very simple induction argument and the above text). I.e., the neurons in your brain would produce a substance that makes phagocytes want to eat them upon rather mild exposure.

Does this help you see the difference?
 
One thing I found quite interesting last time I really looked into the processes behind amphetamine class drugs' neurotoxicity is that most if not all of them really effect protein clearance in the cell via inhibition of the 26S proteasome (ubiquitin proteasome system or UPS) and autophagy in time and concentration dependent manners. Now I'm not entirely convinced that this is a pathway that can be addressed specifically, but lipid soluble antioxidants appear to be favorable options in preventing most of the negative processes that occur with these protein clearance pathways. It basically seems to be:

1) ROS and RNS damage proteins and proteasome subunits

2) Small damaged proteins are targeted to the UPS but cannot be broken down due to damage to the UPS

3) Ubiquitinated proteins aggregate, often with internalized beta-arrestin complexed dopamine receptors. Alpha synuclein is present in these inclusions and appears to aggregate as a way of absorbing reactive compounds, thus having an early protective role.

4)Some of these lys-48 ubiqutinated aggregates localize to the mitochondria and activate stress pathways

5) Aggregates and damaged mitochondria are enveloped into autophagosomes and targeted to the lysosome via p62

6)Due to LAMP-2 dysfunction via unknown mechanisms autophagosomes cannot merge with the lysosome and accumulate, also increasing levels of p62
p62 is really good at inhibiting the UPS thus causing a feedback loop

7)At some point PKC-delta goes from pro-survival to pro-apoptosis due to sustained stress signals, caspase-3 is involved in this step so it is unclear how much is a cause of caspase-3 activation and how much is a consequence. ROCK2, another protein involved in committing a cell to apoptosis, would likely be cleaved by caspase-3 at this point.

8 ) Apoptosis

So this is just one pathway that seems to be relevant, and it is likely going to be effected by other pathways. Thought I would condense my OP into a more digestible form.
 
Epsilon Alpha said:
One thing I found quite interesting last time I really looked into the processes behind amphetamine class drugs' neurotoxicity is that most if not all of them really effect protein clearance in the cell via inhibition of the 26S proteasome (ubiquitin proteasome system or UPS) and autophagy in time and concentration dependent manners. Now I'm not entirely convinced that this is a pathway that can be addressed specifically, but lipid soluble antioxidants appear to be favorable options in preventing most of the negative processes that occur with these protein clearance pathways. It basically seems to be:

1) ROS and RNS damage proteins and proteasome subunits

2) Small damaged proteins are targeted to the UPS but cannot be broken down due to damage to the UPS

3) Ubiquitinated proteins aggregate, often with internalized beta-arrestin complexed dopamine receptors. Alpha synuclein is present in these inclusions and appears to aggregate as a way of absorbing reactive compounds, thus having an early protective role.

4)Some of these lys-48 ubiqutinated aggregates localize to the mitochondria and activate stress pathways

5) Aggregates and damaged mitochondria are enveloped into autophagosomes and targeted to the lysosome via p62

6)Due to LAMP-2 dysfunction via unknown mechanisms autophagosomes cannot merge with the lysosome and accumulate, also increasing levels of p62
p62 is really good at inhibiting the UPS thus causing a feedback loop

7)At some point PKC-delta goes from pro-survival to pro-apoptosis due to sustained stress signals, caspase-3 is involved in this step so it is unclear how much is a cause of caspase-3 activation and how much is a consequence. ROCK2, another protein involved in committing a cell to apoptosis, would likely be cleaved by caspase-3 at this point.

8 ) Apoptosis

So this is just one pathway that seems to be relevant, and it is likely going to be effected by other pathways. Thought I would condense my OP into a more digestible form.
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I'd love to just know a stack that you'd recommend to those of us who are on it purely for ADD (which I am) as the last thing I want is Parkinson or a stuffed short term memory because of the very thing that is trying to help my focus and memory. I'm really guessing at the moment plucking pieces of information out of threads all over the internet and spend so much money on supplements, some just to find out it's doing more harm than good after it has been updated.

Reduced tolerance to me is just a bonus, the main things is protecting my brain to start with or repairing the damage it has done.

Love to hear this from you EA as you seem to be the most proactive on the subject to protect ones self from harm whilst taking this medication. Again ONLY ADD / ADHD doses.
 
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