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Is VMAT2 the explanation for MDMA "loss of magic"?

avcpl

Bluelighter
Joined
Feb 4, 2009
Messages
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Oh, wise ones in ADD! (And I mean that sincerely!)

I hate to post someone else's theories, but on the other forum it has sat dead for several months now and I want to get someone's take who is more knowledgeable.


This is the article in question:

VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse

http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2010.05906.x/full



And here is the text of member "holdout", his interpretation of the article:

"Intimidating read? :p The nutshell: when you first took a stimulant such as methylone or butylone or MDMA or mephedrone, etc. your susceptibility to neurotoxicity was extremely high due to high incidences of neuroexcitation because your neurons' little storage pockets, (which hold spare neurotransmitters for future use), had large "storage bins" :p the VMAT2 transporter is what that is. it has storage membranes that pump out the neurotransmitters forcibly by the stimulant you take.


so at first you EASILY got an overabundance of them being released because it was your first time. over time as you repeatedly did more stims, your VMAT2 stores became smaller because you have metabolized lots of ur neurotransmitters from pumping them out all over the place. so now you have your tolerance and also causing less neurotoxicity when doing stims because you have less neuroexcitation. after the VMAT2 stores become smaller from prolonged use of stimulants, they dont get big again. overall your brain/body is storing less neurotransmitters even if you take a 1-year abstinence!


some of you may now be picturing how it makes perfect sense if you chart the level of "magic" from before, where it would instantly spike super high, and compared to now, where the peak is not even CAPABLE of reaching the same peak as it reached before because you dont have enough neurotransmitters stored to enable that to happen when the stimulant comes and forces the VMAT2 to secrete.


as a compensatory change towards homeostasis like their publshing touches on, prolonged use of stimulants results in hypersensitivity of receptors that respond to the affected neurotransmitters because the overall volatility of acute neuroexcitability is "permanently" low due to the small VMAT2 stores. so to react to the small acute spikes/secretions, you need to be hypersensitive to them. that is why you are able to function normally again while sober: moved by things, good times / bad times, etc., rather than being a brain-dead zombie. that is also why you can get stressed out easily while coming down off stims and for the few days after that.


"So wait-- if i'm hypersensitive, why do i not have the magic?" dont forget you still have receptor downregulation from prolonged use of stims, so that's another factor that reduces the peak on that chart i visualized above. therefore you can only excite the entire neuron to a certain extent, much lower than before, causing weaker firings to other neurons, and therefore a cascading overall impression of just "blaaah". those who take periods of sobriety have some upregulation of receptors which is why the euphoria is slightly more profound when starting to take stimulants again, but still, your VMAT2 stores are too small to store as much neurotransmitters as before for the peak to reach the "magic" level. your hypersensitivity is pretty much secondary to the fact that your VMAT2 stores are minimal, so being hypersensitive does not mean you are profoundly so -- just a tad.


"so can't i load up on 5-HTP and tyrosine?" FOOL! don't be stupid. you'd be refueling a fire your body put out and maybe kill yourself, but in any case, it's not gonna work cuz the biosynthesis of serotonin and dopamine from availability of precursors/amino acids does not "shove them in all the right places" right off the bat. not all neuronal regions of the brain will be saturated with even distribution and the surplus would just get metabolized quickly without helping much anyway.


so... funny how things work out and give this overall impression of "adaptation" like your body adapted to stims to become unaffected and protect your health by "softening the blow" of acute spikes of neuroexcitation this way and that, but just as a natural failsafe quality of the "architecture". there was no deliberate intention to manipulate changes for your safety :p


moving along, i'm sure the question on everyone's mind is: "how do we get the vesicles big again?" well blocking influences on VMAT2 for a while does not seem to help much, so ... *shrugs*. no one knows of a way (yet?). if a way is found, tjhen i hypothesize that with so much neurotoxicity from stims use and changing the VMAT2 back to normal, you would be chronically inducing a state of psychosis with your perceptions of reality. as in chronic hallucinations galore."



So do you think he is on target with his interpretation? Is there anything that can be done?
 
I think the person you are referencing is really over simplifying. It almost seems like they are totally attributing the "loss of magic" to reduced vesicular capacity.

The situation is a lot more complicated than what is being suggested. I maybe wrong but I thought the actual capacity of monoamine vesicles could vary within a fairly wide margin.

I read the last paragraph twice and I have no clue how he came to that conclusion or even what he is talking about :S
 
I don't want to be a dick but...

oh what am I saying, yes I do. That person is expressing his retardery and it's caused retardation in retardville.

Read studies not moronic simplifications.
 
This doesn't make any sense. Size of intra-synaptic vesicular stores is not a known mechanism of tolerance to recreational drugs (nor something under ready metabolic control). Downregulation of endogenous syntheses of neurotransmitters comes only with specific inhibition or downregulation of enzymes involved in such syntheses (or limits placed upon ready availability of precursor).

Ummm...someone post something useful soon, or this thread gets closed. :p

ebola
 
This doesn't make any sense. Size of intra-synaptic vesicular stores is not a known mechanism of tolerance to recreational drugs (nor something under ready metabolic control). Downregulation of endogenous syntheses of neurotransmitters comes only with specific inhibition or downregulation of enzymes involved in such syntheses (or limits placed upon ready availability of precursor).

Ummm...someone post something useful soon, or this thread gets closed. :p

ebola

Feel free to close it! I appreciate the comments.

I often get sucked in to the madness of some posters because I am ignorant of many of the technical details of studies. I wish the ADD members and mods would invade the other forums periodically and stamp "BULLSHIT" on some of the pseudoscience posts that are garnering attention (though that may be a full-time job!) :)
 
loss of 'magic' with MDMA is surely a psychological matter rather than anything to do with brain chemistry in my humble opinion...
 
Decreased dopamine, tyrosine hydroxylase, and DAT, but normal VMAT (!) and DOPA decarboxylase levels in human methamphetamine users.
http://www.nature.com/nm/journal/v2/n6/abs/nm0696-699.html

VMAT is decreased by meth administration in mouse/rat/primate. This is definitely a major difference that calls into question the validity of extrapolating from these models...

Epsilon Alpha, you mentioned in that thread that immune response is related to amph's effects on the brain. Isn't that a given, though, with amph's microglia activation?

...the hell?
http://www.springerlink.com/content/p6753g35n6521230/
http://www.ncbi.nlm.nih.gov/pubmed/18815269
http://www.jneurosci.org/content/22/20/8951.abstract
http://neuro.cjb.net/content/28/39/9850.short

Looks like VMAT2 is initially downregulated (bad) then upregulated (good) in humans. But this study (comparing VMAT2 in amphetamine vs cocaine in rats) suggests that the localization of vesicles may change with acute or subacute usage. http://www.sciencedirect.com/science/article/pii/S0014299902019854
Well we'll get a better idea when this study comes out http://search.engrant.com/project/y3xUhm/pet_imaging_study_of_brain_vmat2_in_human_methamph etamine_users

I could be wrong here, but maybe VMAT2 is only implicated in toxicity because of a secondary effect on vesicle transport within the cell. That would explain some of the weirder results, but I'm not 100% on it. Methamphetamine appears to keep vesicles away from the synapse, while cocaine appears to lead to more vesicles being close to the synapse. Not sure if MPH could have the same effect as cocaine, but if so it might be a good idea to cycle AMP and MPH at least on paper...

However there are also a giant stew of other proteins and signals involved in long term amphetamine use. One thing I'm still trying to figure out is how amphetamine but not MCAT activates glial cells, hopefully someone with more expertise in the field of immunology can help me out here.

A post from the "Amphetamine Neurotoxicity Reduction/Prevention II" thread. Redistribution of VMAT2 may be a possible cause of some amphetamines' tolerance profiles.
 
Thought I'd add that lithium is known to upregulate VMAT2 in most brain regions, might be worth a look at again. It got some pretty decent reviews from a few bipolar stimulant users but n=3 and its far from an ideal place to extrapolate from.
 
I wish the ADD members and mods would invade the other forums periodically and stamp "BULLSHIT" on some of the pseudoscience posts that are garnering attention (though that may be a full-time job!)

Seconded. It's astounding some of the bullshit that is taken as scientific fact in various sub-forums.
Having a mod with ADD level knowledge for certain forums, OD for example would be greatly beneficial.
As incorrect information could be pointed out & corrected by a mod potentially greatly increasing HR efforts.
However, this is off topic & as such I digress. That comment seemed to warrant more attention IMHO so figured I'd point it out.
Thanks to any mods that notice & take into consideration said comment. I apologize for going off topic & shall take my leave with a parting thanks.
 
After treatment of PACAP38, animals were given a neurotoxic regimen of METH and assayed for neurochemistry two days later. Animals treated with four doses of 5 mg/kg METH exhibited a 72% loss of striatal DA, down to 6.18 ± 0.42, whereas those animals pretreated with PACAP38 only lost 62%, reduced to 8.27 ± 0.28 (n = 6–8; p < 0.05). Furthermore, animals administered one dose of 20 mg/kg METH lost 60% of striatal DA, decreased to 9.39 ± 0.74, but PACAP38 pretreated animals lose 50%, down to 11.42 ± 0.97 (n = 6–8; p < 0.05; Figure 3A

Not exactly a big improvement....

Also, it's a peptide that needs to be injected.
 
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