MDAI + amphetamine neurotoxicity

[atrollappears]

So, I was looking into combining MDAI and amphetamine as a possible MDMA/methylone/whatever replacement with the added benefit of being non-neurotoxic, when I came across this study which really bummed me out.
http://www.sciencedirect.com/science/article/pii/009130579190106C
I was wondering if anyone had an explanation for this effect (since I was sure that neurotoxicity was due to the specific metabolites of the chemical involved being toxic to their respective type of monoamine cell and am now very confused), or has access to the journal and so can tell me what doses they actually used (probably beyond what I'd do with the amphetamine, but just to make sure).

 

[cannibalsnail]

Its because any simultaneous release of 5-HT and DA causes oxidiative stress inside the Serotonin neuron.

That said non amphetamine releasers with MDAI are still less neurotoxic than respective doses of MDMA because they won't metabolise into toxic metabolites such as Alpha-methyl-dopamine.

 

[dip12]

with the added benefit of being non-neurotoxic

This is one of the biggest inaccuracies in circulation. These compounds were 'explored as'/'investigated as' non-neurotoxic analogues, but these papers really do nothing to address potential neurotoxicity. These compounds are innocent until proven guilty and really nothing is known about them. It's perfectly plausible that a whole host of neurotoxic effects occurs - we just have so little scientific let alone clinical research on them we have no evidence of such effects.

Is ONE research paper quoting a new chemical entity as potentially non-neurotoxic all it takes? This is very misleading terminology. I also personally feel MDAI feels like it has some nasty after effects so I am in complete disbelief that this compound is innocent (this is separate from the likely neurotoxicity in combination with amphetamine etc)

 

[atrollappears]

This is one of the biggest inaccuracies in circulation. These compounds were 'explored as'/'investigated as' non-neurotoxic analogues, but these papers really do nothing to address potential neurotoxicity. These compounds are innocent until proven guilty and really nothing is known about them. It's perfectly plausible that a whole host of neurotoxic effects occurs - we just have so little scientific let alone clinical research on them we have no evidence of such effects.

Is ONE research paper quoting a new chemical entity as potentially non-neurotoxic all it takes? This is very misleading terminology. I also personally feel MDAI feels like it has some nasty after effects so I am in complete disbelief that this compound is innocent (this is separate from the likely neurotoxicity in combination with amphetamine etc)

http://www.ncbi.nlm.nih.gov/pubmed/1967651

Its because any simultaneous release of 5-HT and DA causes oxidiative stress inside the Serotonin neuron.

That said non amphetamine releasers with MDAI are still less neurotoxic than respective doses of MDMA because they won't metabolise into toxic metabolites such as Alpha-methyl-dopamine.

So if it's just the combination of 5-HT and DA release, then why doesn't the DA uptake inhibitor cause damage to 5-HT sites? Would you explain that as DA levels simply not increasing enough?
And can you explain why there seems to be this sort of dual-condition for inducing 5-HT neurotoxicity (increase in 5-HT and DA levels AND the formation of toxic metabolites)? I really question the dopamine theory, it was my impression that it had been pretty much disproved. I just want to know why amphetamine which has virtually no serotonergic properties below basically lethal doses is making metabolites that seem to be affecting the 5-HT system. Do these metabolites have affinity for SERT?
Edit: I'm pretty sure it's not just the dual 5-HT/DA release. I'm not able to find a study on this for serotonin neurons but I'm pretty sure I remember toxicity also not resulting in those. http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2011.07632.x/full

 

[cannibalsnail]

Essentially dopamine enters the Serotonin transporter and gets metabolised by MAO into oxygen radicals which damage the neuron. Reuptake inhibitors do not release any dopamine just raise levels in the synaptic cleft so no toxicity occurs.

 

[atrollappears]

Mmm I'm not sure I buy it. I seem to recall this theory falling out of favor with researchers, but I can't remember why. But accepting that this is true, why, then, are PAL-287 and 4-FA not neurotoxic?

 

[Poodles!]

http://www.ncbi.nlm.nih.gov/pubmed/1967651
So if it's just the combination of 5-HT and DA release, then why doesn't the DA uptake inhibitor cause damage to 5-HT sites? Would you explain that as DA levels simply not increasing enough?http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2011.07632.x/full

I'd be interested to see data on NDRI's combined with SSRA's to see if they cause toxicity in the same way as releasers. Other non-amphetamine doperminergics too. 4-MAR releases serotonin and dopamine yet most studies find it to not be neurotoxic. I'm pretty sure toxic metabolites of amphetamine would have affected their results too, so the toxicty won't be soley down to dopamine release.

 

[ebola?]

So if it's just the combination of 5-HT and DA release, then why doesn't the DA uptake inhibitor cause damage to 5-HT sites?

In Nichols et. al' study, the researchers chose a DA releaser that actually has a low ceiling of efficacy, so generalization is quite unclear. But DA releasers are just way, way more effective at increasing intersynaptic DA than DARIs.

ebola

 

[atrollappears]

I'd be interested to see data on NDRI's combined with SSRA's to see if they cause toxicity in the same way as releasers. Other non-amphetamine doperminergics too. 4-MAR releases serotonin and dopamine yet most studies find it to not be neurotoxic. I'm pretty sure toxic metabolites of amphetamine would have affected their results too, so the toxicty won't be soley down to dopamine release.

I believe the study tested that and found that the DRI did not create neurotoxicity when combined with MDAI. But as ebola said, releasers have multiple times the effectiveness of reuptake inhibitors in increasing DA levels. And as far as MAR goes... yes, wouldn't that be a wonder drug, if it didn't terminally fuck your heart a la fenfluramine/aminorex. An interesting point about the 5-HT2B receptor (which, if you didn't know, causes that heart damage when activated by an agent like aminorex, fenfluramine, MAR, MDMA, etc): 5-HT2B receptor activation actually plays a big part in serotonin release (maybe dopamine too, can't remember) and MDMA's rewarding effects are actually dependent on 5-HT2B activation...
I'm starting to believe that for any drug to produce reliably and substantially positive effects, it has to in turn swell your heart valves like a balloon, fry one or more of your monoaminergic systems, throw your hormones out of balance, and/or produce massive physical and/or psychological addiction. *sigh* maybe psychedelics are just the way to go...

In Nichols et. al' study, the researchers chose a DA releaser that actually has a low ceiling of efficacy, so generalization is quite unclear. But DA releasers are just way, way more effective at increasing intersynaptic DA than DARIs.

ebola

Yes indeed. It would be interesting to see them try 2-AI or something of the like instead of a DA releaser that is a known neurotoxin. I wish I could see the doses they used :/ probably something absurd but I want to assess the relative risk of this combination as far as neurotoxicity goes.