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Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

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Well, I do get the impression that PDE5 inhibitors are great for the amph comedown. I feel like my blood is flowing again, maybe its purely psychological, but I think not.

I don't have MSN you douche, and I know you're lazy. You're telling me you don't have a gmail account?...If not you better get one.
 
Ok epsilon alpha help me out on this shit.

I may be completely off but:
Dopamine doesnt cause reward itself; DRI's do cause reward wich is trough the mu opiate receptors.

I know from my shizo past that opiates dont work unless combined with a DRI.
I also know that cGMP is required for reward and is rewarding itself.

How does this all fit togheter?
I think PDE inhibitors may be the key for anhedonia and sa related issues as they modulate both dopamine and cGMP so mu is able to operate.

Srry for all this scattered shit; again may be completely off but have been compiling some shit here; its another of my too optimistic posts where you cant make def conclusions off but optimism often wins.
http://www.longecity.org/forum/topic/56694-pde10-inhibitor-and-its-potential-uses/

Ill pm you
Well gCMP is rewarding atleast according to cpp study's and all the shit.
 
Brain Res Bull. 2010 Apr 5;81(6):549-51. Epub 2009 Dec 14.
Selective D1 agonism but not D2 antagonism is reflected in cAMP and cGMP levels in rat CSF.
Torremans A, Van Hemelrijck A, Straetemans R, Vanhoof G, Van Den Kieboom G, Drinkenburg WH.
Source
Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica NV, 2340 Beerse, Antwerp, Belgium. [email protected]
Abstract
Cyclic adenosine 3'5'-monophosphate (cAMP) and cyclic guanosine 3'5'-monophosphate (cGMP) serve as second messengers in several cellular pathways within the central nervous system. In various neurological and psychiatric disorders with known deficits in neurotransmission function, CSF levels of cAMP and/or cGMP in patients were studied. Very little information is currently available on cAMP and cGMP levels in CSF of animals. Moreover, this is the first study on the effects of pharmacological treatment on cAMP and cGMP levels in rat CSF. Effect of systemic treatment with a D1 receptor agonist SKF82958 and a D2 receptor antagonist haloperidol on cAMP and cGMP levels, as well as baseline cAMP and cGMP levels in CSF of rats was determined. A significantly increased cAMP and cGMP level in cisternal CSF of rats systemically treated with the D1 receptor agonist SKF82958 was observed, while when treated with the D2 antagonist haloperidol, no effect on cAMP and only a slight decrease of cGMP was observed after treatment with the highest dose. Determining cAMP and/or cGMP in CSF of experimental animals can serve as a useful tool to study neural processes affected by disease and treatment.
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Shizo --> hypo D1 and hyper D2 --> Depleted levels of camp and cgmp --> Immume to mu related pleasure. However opiates witch induce cGMP and cAMP still arent working and research shows da needs to be active before reward can take place.

PDE inhibition may normalise all this, perhaps...
Its interesting studying pde; camp and cgmp tough they are implicated in alot of things.
 
MeDieViL said:
@Dextermeth
Piracetam appears to act on nmda but not only that also on AMPA; because of acting on AMPA it increases the activation of the nmda receptor so basicly it potentiates itself by acting on AMPA too.
Click to expand...

Is piracetam the only nootropic racetam that exerts this action?
 
"Amphetamine effect on the choline concentration of human cerebrospinal fluid'
-----

Abstract
The choline concentration of the lumbar cerebrospinal fluid of amphetamine dependent subjects has been measured during amphetamine intoxication and after detoxification. It was found that the choline level was significantly higher during the intoxication period than after. The results are discussed in view of the known amphetamine effect on the acetylcholine release from brain cortex.

So is choline to be avoided while on amps or what?
 
Not neccesarily, amphetamine releases lots of norepinephrine etc. but tyrosine supplementation doesn't seem to have any harm.

Your body has lots of feedack mechanisms to help it keep the right levels of neurotransmitters derived from dietary nutrients, like choline and the monoamines. This explains why you can eat things like soy lecithin and not have them be directly psychoactive.
 
Does anyone have the free fulltext for the MDMA+viagra in rats/mice study?
I really want to see what it has to say.

NO. appears to be rather central in the whole process from NDMA to epigenetic CNS changes.
 
Epsilon, the histone deacetylase inhibition has led me to a frightening conclusion, you focus mainly on curcumin but..

Psychiatry and neurology

HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics. The prime example of this is valproic acid, marketed as a drug under the trade names Depakene, Depakote, and Divalproex. In more recent times, HDIs are being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.[11] Enhancement of memory formation is increased in mice given the HDIs sodium butyrate or SAHA, or by genetic knockout of the HDAC2 gene in mice.[12] While that may have relevance to Alzheimer's disease, it was shown that some cognitive deficits were restored in actual transgenic mice that have a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins.[13]
Cancer treatment

from wikipedia


this has connected a few puzzle pieces regarding why I was able to continue on just a 1mcg ULD NLTX, ~15mg dxm 300mg gabapentinx3 daily (later pregbalin 100mg x3) and 120 mg codeine which kept my tolerance and the euphoria at a minimum, with discontinuation of the pregbalin I was no longer able to even get remotely close euphoric effects from opiates without much higher levels.

And the reason being? anti epileptics, benzos, ethanol, all appear to affect histone activity thus stopping these epigenetic changes.. it doesnt make sense though, because the study is claiming HDI action increases memory formation with sodium butyrate- but we all know these drugs have the opposite effect from another mechanism of action ?

What is going on exactly..
 
Sorry for the brief reply I'm on my phone , but it appears to me that all the commonly available HDAI's are dirty as hell. Curcumin was my main focus as its easily available and has a stellar safety record.

Most of the mood stabilizers and ethanol have significant effects on the GABAgenic system which would explain some of their negative cognitive effects. I'm extremely interested in NO's effect on the epigenome right now.
 
So my laptop is currently in for repairs, hence the whole link free replies lately. But, it looks like the KEY or at the very least central component to the whole amphetamine tolerance and neurotoxicity issue is NO.

Literally every other major pathway from epigenetic changes, to NMDA dependent tolerance appears to worth through it or be effected by NO.
Currently chipping away at my MCAT and the next thread's OP's

And with that I ask you all to please dump free full texts for me :D
 
Yet another big ol link dump! Epigenetics, NMDA, gap junctions, and NOS! Oh my!

http://www.jneurosci.org/content/20/6/2332.full.pdf
http://onlinelibrary.wiley.com/doi/10.1196/annals.1316.027/abstract
http://www.ncbi.nlm.nih.gov/pubmed/10482402
http://www.sciencedirect.com/science/article/pii/S0301008299000386 (basal cNOS vs iNOS)
http://www.sciencedirect.com/science/article/pii/S001429990302524X
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2000.tb05193.x/abstract (author directly looks at methamphetamine)
http://www.ncbi.nlm.nih.gov/pubmed/15337264 (points to a microglial connection)
http://www.landesbioscience.com/journals/cbt/NottCC8-5.pdf (details how NO modifies the epigenome in developing neurons, implications for stem cells? Also, details CREB interaction)
http://www.ncbi.nlm.nih.gov/pubmed/11585554 (It appears to be mediated via dopagenic transmission and produces biphasic effects on nNOS expression)
http://www.nature.com/ncb/journal/v3/n2/abs/ncb0201_193.html (some reading on a potentially relevant additional NO signalling pathway)

And, to show I'm not totally biased towards my own hunches:
http://csbn.concordia.ca/faculty/amir/docs/Stewart-Brain Res 641 (1994).pdf
Not entirely sure I like how it was conducted, L-NAME has a really really short effective half life in the body which could explain the results
 
Epsilon Alpha said:
Yet another big ol link dump! Epigenetics, NMDA, gap junctions, and NOS! Oh my!

http://www.jneurosci.org/content/20/6/2332.full.pdf
http://onlinelibrary.wiley.com/doi/10.1196/annals.1316.027/abstract
http://www.ncbi.nlm.nih.gov/pubmed/10482402
http://www.sciencedirect.com/science/article/pii/S0301008299000386 (basal cNOS vs iNOS)
http://www.sciencedirect.com/science/article/pii/S001429990302524X
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2000.tb05193.x/abstract (author directly looks at methamphetamine)
http://www.ncbi.nlm.nih.gov/pubmed/15337264 (points to a microglial connection)
http://www.landesbioscience.com/journals/cbt/NottCC8-5.pdf (details how NO modifies the epigenome in developing neurons, implications for stem cells? Also, details CREB interaction)
http://www.ncbi.nlm.nih.gov/pubmed/11585554 (It appears to be mediated via dopagenic transmission and produces biphasic effects on nNOS expression)
http://www.nature.com/ncb/journal/v3/n2/abs/ncb0201_193.html (some reading on a potentially relevant additional NO signalling pathway)

And, to show I'm not totally biased towards my own hunches:
http://csbn.concordia.ca/faculty/amir/docs/Stewart-Brain Res 641 (1994).pdf
Not entirely sure I like how it was conducted, L-NAME has a really really short effective half life in the body which could explain the results
Click to expand...


So, how can we use this information to reduce or prevent tolerance to amphetamines?
 
Tussmann said:
So, how can we use this information to reduce or prevent tolerance to amphetamines?
Click to expand...

This like most of the stuff I'm still sitting on isn't refined enough for me to give any suggestions right now, but it does help tie in NMDA antagonists in with epigenetic changes as well as neuro-inflammation/microglial activation. What it does show its that if we start digging around NO we may find a central piece of the puzzle for both tolerance and toxicity.

Other than that amphetamine may change gap junction function so that groups of neurons are more likely to fire in all-or-nothing bursts, potentially giving another reason to look at modafinil for amphetamine withdrawal. It also suggests that low dose modafinil might be a place to look, hell the stuff is even neuroprotective in combination with methamphetamine according to some animal studies.

Some reading on the role of the NMDA-NOS connection: http://www.jbc.org/content/269/17/12645.short
Cholecystokinin-NMDA-NOS relationship: http://www.anesthesia-analgesia.org/content/91/1/110.short
 
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Would anyone mind educating me on what is so special about blueberries please. They have been mentioned a few times in this thread but my knowledge of them was that their antioxidant content was less than that of coffee and cacao. Is there a magical ingredient that I don't know about?
 
There is much I do not understand about these substances and I would like to know a little more because there are some possible issues with consuming the 2/3/4-fluoroamphetamines. There is little information on available on the specific drugs but perhaps by applying some psychopharmacological principles it's is possible to assess their long term safety. I have read every thread on bluelight concerning 2-fa but my lack of knowledge makes the process of putting all the jigsaw puzzle pieces together problematic.

2-fluoroamphetamine:
2-Fluoroamphetamine.png


Wikipedia is telling me that

The high reactivity of fluorine means that once it does react with something, it bonds with it so strongly that the resulting molecule is very inert and non-reactive to anything else.
Click to expand...

Now does this make 2-fa just dextroamphetamine with a fluorine added? Would you consider 2-fa safe because of the strength of the C-F bond? Am I committing unintentional suicide if I consume 2-fa regularly?

tyvm
 
Quick question:
I'm prescribed Wellbutrin 300mg/day for depression and from what I've read it's apparently an amphetamine? If anyone could clarify it'd be much appreciated. And if it is, should I be worried about neurotoxicity?
 
Re: Fluoroamphetamine toxicity, fluorine bonds are incredibly hard to remove on organic compounds without essentially burning the molecule down. Fluorocarbons are actually often praised for their non-reactivity.

Even if, through some freak process, your body removed fluoride from the amphetamine, a dose of amphetamine would have something like 1-10mg of fluoride. You get more than that in a dose of toothpaste.

Re: Wellbutrin, buproprion is a lot closer to a cathinone and shouldn't be considered an amphetamine.
 
sekio said:
Re: Fluoroamphetamine toxicity, fluorine bonds are incredibly hard to remove on organic compounds without essentially burning the molecule down. Fluorocarbons are actually often praised for their non-reactivity.

Even if, through some freak process, your body removed fluoride from the amphetamine, a dose of amphetamine would have something like 1-10mg of fluoride. You get more than that in a dose of toothpaste.

Re: Wellbutrin, buproprion is a lot closer to a cathinone and shouldn't be considered an amphetamine.
Click to expand...

The biggest issue with the fluoroamphetamines is that they might have some weird toxicity that the SAR just doesn't predict. Look at the toxicity gap between methamphetamine and regular amphetamine and all the various other derivatives.

The amphetamine backbone is a very gifted structure, so relatively small changes in it can result in say an antidepressant/psychedelic/stimulant/toxic nightmare ala PMMA.
 
pro(phet)(fit) said:
Now does this make 2-fa just dextroamphetamine with a fluorine added? Would you consider 2-fa safe because of the strength of the C-F bond? Am I committing unintentional suicide if I consume 2-fa regularly?
Click to expand...

Given that the para-halogenated amphetamines exhibit neurotoxicity not fully explained by their potency as trimonoamine releasers, some hesitancy with ring-halogenated compounds in general seems warranted. However, when the halogen in question is fluorine and when affinity for SERT is nearly nil, we should expect reduced toxicity.

ebola
 
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