Insufflation and plugging to avoid MDMA neurotoxicity? And diff. in tolerance for ROA

[snortmdma]

I have read in other forums and in research articles (sorry I am not going to take the time to provide links, but if you search google documents you can find them) that MDMA neurotoxicity is caused by metabolites formed in the stomach. Another study I read said that injecting MDMA directly into the brain avoids all neurotoxicity. My question is this: If one insufflates or plugs MDMA, then the metabolites wouldn't form because the stomach would be bypassed, so wouldn't neurotoxicity not be an issue? Also, what are the differences (if any) relating to tolerance for insufflation vs. plugging vs. swallowing? It seems to reason that if neurotoxicity is avoided by using these two ROAs then tolerance would be lessened, right?

 

[JWills20]

I have read in other forums and in research articles (sorry I am not going to take the time to provide links, but if you search google documents you can find them) that MDMA neurotoxicity is caused by metabolites formed in the stomach. Another study I read said that injecting MDMA directly into the brain avoids all neurotoxicity. My question is this: If one insufflates or plugs MDMA, then the metabolites wouldn't form because the stomach would be bypassed, so wouldn't neurotoxicity not be an issue? Also, what are the differences (if any) relating to tolerance for insufflation vs. plugging vs. swallowing? It seems to reason that if neurotoxicity is avoided by using these two ROAs then tolerance would be lessened, right?

I'm pretty sure you're completely misinterpreting this. In order for MDMA to leave the body, it must be metabolized. Some of these metabolites can be damaging (the neurotoxicity theory). But, I'm pretty sure that however you take it won't change the way it is metabolized excreted from the body. The way you take it changes how it's initially metabolized and sent to the brain, but wouldn't change the metabolites its converted into for removal. Snorting, insufflation and plugging all hit faster because it gets into the blood stream quicker than oral. Bypassing the stomach is unlikely to avoid MDMA from being converted into it's usual metabolites for removal.

Post the studies you've read?

Welcome to BL.

 

[snortmdma]

thanks for the reply jwills20. here is an abstract for the study claiming that brain injection avoids neurotoxicity, which would contradict what you say about how when it leaves the body it would cause neurotoxicity, because it still would have to leave the body when you inject into brain, right? here is another study abstract saying that subcutaneous admin. didn't cause reduction in 5ht uptake sites, but oral admin DID. This would support the hypothesis that if you bypass the stomach, you avoid neurotoxicity. Also, does anyone reading this know how different ROA's affect tolerance? Because it seems that by avoiding reduction in 5ht uptake sites via bypassing the stomach would lessen tolerance, right?

• Title: 3,4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, when administered centrally at a concentration occurring following a peripherally injected neurotoxic dose
  
• Author: Esteban, Blanca ; O'Shea, Esther ; Camarero, Jorge ; Sanchez, Veronica ; Green, A. Richard ; Colado, M. Isabel
• Subjects: 3,4-Methylenedioxymethamphetamine Microdialysis 5-Hydroxytryptamine Neurotoxicity Hyperthermia Dopamine 5,7-Dihydroxytryptamine
• Is Part Of: Psychopharmacology, 2001, Vol.154(3), pp.251-260 [Peer Reviewed Journal]
• Description: Rationale: There is good evidence that 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicityresults from free radical formation. However, it is unclear whether it is the presence of MDMA or a metabolite in the brain that initiates this process. Objective: We wished to measure the concentration of MDMA in the brain following peripheral administration of neurotoxic doses and examine the effect on acute monoamine release and the subsequent neurotoxic loss in 5-hydroxytryptamine (5-HT) content when a high concentration of MDMA was infused into cerebral tissue. Methods: Selectively placed microdialysis probes were used to determine both the concentration of MDMA in the brain following peripheral injection and the degree of 5-HT release. Monoamines in dialysate and tissue were measured with standard HPLC techniques. Results: MDMA, administered intraperitoneally, at doses of 10 and 15 mg/kg, which produce neurodegeneration, resulted in an estimated cerebral extracellular concentration of MDMA of 11 and 20 µM, respectively. When MDMA (100–400 µM) was perfused through a selectively placed microdialysis probe it dose-dependently increased 5-HT release in the hippocampus and dopamine release in the striatum. Seven days after perfusion of MDMA the concentration of 5-HT and its metabolite, 5-hydroxyindoleacetic acid was unchanged in the ipsilateral side of the brain of normothermic rats and also in the brains of animals made hyperthermic to mimic the acute effect of MDMA given peripherally. In contrast, perfusion with 5,7-dihydroxytryptamine (400 µM) markedly decreased the cerebral 5-HT content. A second probe, also placed in the hippocampus at a distance of 1 mm from the main probe, revealed that during the perfusion of MDMA (400 µM) the estimated extracellular concentration of MDMA in the hippocampus was between 10.4 and 19.5 µM, i.e. in the range of concentrations observed after systemic injection of neurotoxic doses of MDMA. Conclusions: These data demonstrate that MDMA when injected directly into the brain produces 5-HT release but no neurotoxicity, suggesting that it must be metabolised peripherally in order to produce compounds that induce free radical formation and neurotoxicity in the brain.
• Language: English
• Source: Springer Science & Business Media B.V.

• Title: Evidence that both intragastric and subcutaneous administration of methylenedioxymethylamphetamine (MDMA) produce serotonin neurotoxicity in rhesus monkeys
  
• Author: Kleven, Mark S. ; Woolverton, William L. ; Seiden, Lewis S.
• Subjects: Serotonin ; Neurotoxicity ; 3,4-Methylenedioxymethamphetamine ; Primate
• Is Part Of: Brain Research, 1989, Vol.488(1), pp.121-125 [Peer Reviewed Journal]
• Description: It has been demonstrated that repeated, subcutaneous administration of 3,4-methylenedioxymethamphetamine (MDMA) to rats, guinea pigs, and squirrel monkeys produces long-lasting depletions of serotonin (5-hydroxytryptamine; 5-HT) in several brain regions. Since evidence of degenerating 5-HT neurons has been observed in the rat brain following MDMA injections, it islikely that these depletions are due to neurotoxicity similar to that observed with other substituted amphetamines. The purpose of the present study was to determine if MDMA produces similar evidence of neurotoxicity in rhesus monkeys when administered by either the intragastric (i.g.) or subcutaneous (s.c.) route. Administration of MDMA (5.0 mg/kg/12 h × 4 days) by either i.g. or s.c. routes depleted 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in various brain regions 2 weeks after the last injection. Further, a significant decrease in [ 3H]5-HT uptake sites inthe hippocampus was observed in monkeys treated with MDMA by the i.g. route. Reductions in uptake sites did not achieve statistical significance when drug was administered s.c. The results suggest that repeated administration of MDMA produces long-lasting, potentially neurotoxic effects on central 5-HT neurons in primates and does so when given orally.
• Language: English
• Source: SciVerse ScienceDirect Journals

 

[JWills20]

^Tis an interesting hypothesis. I see what you mean now and it does make sense. If you can bypass peripheral processing (the first study), and specifically intragastric metabolism (second study), it does seem to remove neurotoxicity suggesting that the mechanism is mediated by intragastric production of toxic metabolites. I guess the main problem is the fact that MDMA has not been shown to cause marked neurotoxicty at recreational doses in humans, so these super high dose studies aren't all that relevant. Well, unless something new is out there that I haven't seen yet (haven't researched it much for a year or two).

Regarding tolerance, I'm not sure whether tolerance reflects neurotoxicity and 5-HT downregulation. I think the mechanisms of tolerance go way beyond that.

 

[snortmdma]

thanks jwills. I do think that 5ht receptor down regulation is a big cause of tolerance, though, since mama's effects arise from activation of these receptors, and MDMA causes transient down regulation of them. On tolerance, can you explain a little the mechanisms that you are referring to? Also do you know of a way to reduce tolerance, making it possible to roll harder with shorter breaks between rolls?

 

[Mazzab]

Also do you know of a way to reduce tolerance, making it possible to roll harder with shorter breaks between rolls?

I'll have my cake...and I'll eat it too. Lol. Don't attack mdma this way. It's only a recipe for disaster. Proper time between doses and reasonable dosing when your are rolling. Avoid re dosing

 

[JWills20]

thanks jwills. I do think that 5ht receptor down regulation is a big cause of tolerance, though, since mama's effects arise from activation of these receptors, and MDMA causes transient down regulation of them. On tolerance, can you explain a little the mechanisms that you are referring to? Also do you know of a way to reduce tolerance, making it possible to roll harder with shorter breaks between rolls?

Well, and this is just a personal hypothesis, I think that tolerance is a downstream decrease in response from similar release of 5-HT. Serotonin is one of the highest cognitive functions governing a lot of other systems. That is, it plays a large role in the down-stream release of oxytocin, prolactin and dopamine. While MDMA is an amphetamine and does thus serve to directly release some DA, it is also thought that a portion of the DA release is a result of 5-HT2 activation. My personal theory is that connectivity of these systems becomes weaker with MDMA abuse (and perhaps even use). So, while MDMA's effect on serotonin is similar (but probably is also somewhat decreased), the spike in serotonin doesn't set off the same downstream cascade of neurotransmitter release, therefore you don't get as high and perhaps feel like you're 'losing the magic'. It makes sense from a practical perspective, because some people take more and more doses of MDMA trying to get the high which just doesn't arrive. If it was simply reductions in 5-HT then one would expect increased dosing to work.

Note that this is just my idea based upon my limited knowledge of how MDMA works, and my own intuition.

 

[Deleted member 290563]

with the irreproducibility of biological research, i wouldn't say that one journal publication likely means anything at all. Now if this is something that has been studied and demonstrated by a few different research groups then i might take it to heart.

 

[JWills20]

with the irreproducibility of biological research, i wouldn't say that one journal publication likely means anything at all. Now if this is something that has been studied and demonstrated by a few different research groups then i might take it to heart.

Unless you have any reasons to dispute their results, other than simply the lack of reproduction (and we don't even know that really, unless you've broadly searched for literature), then you can't just dismiss their findings. All known and reproduced facts were once novel findings too.

 

[Deleted member 290563]

i'm not saying they are wrong, and I'm not saying this topic hasn't been researched by other groups, i havn't bothered to look. I'm just saying take the one single abstract you read in the absence of further research or literature searches with a grain of salt