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I have a dubious theory

TheAzo said:
Cocaine is a DA reuptake inhibitor, it does not release DA.

There are some
Click to expand...

I was under the impression that it did both. So if it inhibited Dopamine reuptake, wouldn't that increase synaptic DA and neurotoxicity(from that source)? Would the depletion of dopamine or the increase have more effect? since I was thinking of timing the "crash" comedown of the coke with the comedown of the mdma, I would assume that the net effect during the relevant time period would be DA depletion.

As for the downregulation, as far as my limited knowledge goes(someone who knows feel free to correct me), DA recovery is much faster than 5HT, however over DA-stimulation can cause permanent receptor neuron death unlike 5HT overstimulation which causes prolonged downregulation. Anyone know any better?

I was going to ask if neurotoxicity was glutamate excitotoxicity regulated, would ketamine help regulate that as an NMDA antagonist, or on a more nootropic note, L-Theanine? Then I saw...

From that article as well:
Glutamate Does Not Appear to Play a Major Role in MDMA neurotoxicity

Excitatory amino acids such as glutamate have well-established potential to damage neurons (Choi 1992; Olney 1994). A role for glutamate in MDMA neurotoxicity was suggested by a report that the N-methyl-D-aspartate (NMDA) antagonist, dextrorphan, inhibited MDMA-induced 5HT depletions in the rat striatum (Finnegan et al. 1990). Subsequent studies employing other NMDA antagonists, such as dizocilpine (also called MK-801), have not supported this conclusion. Although it is neuroprotective, dizocilpine appears to protect against MDMA neurotoxicity through a thermoregulatory mechanism (Farfel and Seiden 1995). Glutamate antagonists that do not block MDMA-induced hyperthermia are not neuroprotective (Colado et al. 1998; Farfel and Seiden 1995). As further evidence against a role for glutamate in MDMA neurotoxicity, Nash and Yamamoto (1992) reported that a neurotoxic MDMA regimen had no effect on acute glutamate efflux in the striatum of rats. Finally, excitotoxicity does not usually
produce selective axon loss. Thus, there currently appears to be no strong evidence that glutamate plays in role in the mechanism of MDMA neurotoxicity.

So uh... anyone know ketamine's thermal effect?

Then I saw this:
7. It is concluded that ketamine produces hypothermia in rats possibly through the release of 5-hydroxytryptamine in the hypothalamus and that this effect is similar in some respects to that produced by morphine in non-tolerant rats.
From http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1776151/
 
good theory, but wouldn't it be the same with all dopamine-releasing pychoactives? i don't think releasing more chemicals from your brain is really going to help. it may make less dopamine bind to serotonin, but don't know if they trade off for what the other pychoactives damage does to you.

could be wrong, i'm not expert on this stuff.
 
MDMA is converted into neurotoxic metabolites in the body. No doubt about it. But I absolutely despise this 'explanation.' :)

The problem is that the 'neurotoxic metabolite' theory just replaces the neurotoxic amphetamine you deliberately ingested with another neurotoxic amphetamine that your body formed on its own. That's more of an evasion that an explanation; we already knew that amphetamines (of any sort) tend to be neurotoxic, so it's not actually surprising to find that a (still an amphetamine) metabolite of MDMA is itself neurotoxic.

The other problem I have with this gleeful hunt for a neurotoxic metabolite is that the whole damn line of questioning is based on one old study that injected MDMA into specific parts of the brain of monkeys without producing neurotoxicity. "Well,' they said, "if the drug isn't directly toxic when applied to the brain, then it must be something that's formed elsewhere (a metabolite) doing the damage."

Except we've learned in the years since that overheating is a critical factor in MDMA neurotoxicity; something that those localized injections into the brain rather certainly didn't cause. In other words, viewed through the lens of newer research, there's not actually a good reason to suspect that a toxic metabolite is the sole or primary actor in MDMA neurotoxicity.



My theory remains that MDMA itself is broken down by MAO, creating reactive oxygen species that can (under the right conditions) lead to destruction of the axon.

The funny thing is that nobody seems to have ever closely examined the capacity of MAO to degrade any sort of amphetamine. It's just been assumed since the dawn of pharmacology that it doesn't because amphetamines are orally active (while phenylethylamine is not, since MAO breaks it down too rapidly.)

After all, even if you want to blame a metabolite, you still have to explain how it can create oxidative damage in the axon. Degradation by MAO could explain it.
 
I was actually under the impression that the neurotoxicity was from the MAO degradation of dopamine binding to the serotonin terminals. The resulting peptic acid causes oxidative damage to the terminal. This would explain why several studies have shown that the damage can be prevented/reduced by
1. Antioxidants that pass the BBB
2. MAOIs
3. SSRIs

This would explain the lack of a specific toxic metabolite, and how there is oxidative damage to the axon that is prevented by the above methods.
 
The theory that dopamine breakdown was to blame has been disproven (primarily by research that found that when you remove virtually all of the dopamine from a rat's brain it still gets MDMA neurotoxicity.) See: http://www.erowid.org/references/refs_view.php?ID=1365

This idea was the early favorite, and continues to be widely believed largely due to sites that haven't updated their information (or aren't aware that the theory has been discarded.)
 
TheDEA.org said:
The theory that dopamine breakdown was to blame has been disproven (primarily by research that found that when you remove virtually all of the dopamine from a rat's brain it still gets MDMA neurotoxicity.) See: http://www.erowid.org/references/refs_view.php?ID=1365
/QUOTE]

I'm with you on this one, except that I personally wouldn't say the theory involving dopamine breakdown has been disproven. It's just been shown that DA is not essential for MDMA neurotoxicity. AFAIK the reason this was a popular theory to begin with is owed to findings that high brain DA levels at least exacerbate MDMA neurotoxicity.
Click to expand...
 
TheDEA.org said:
MDMA is converted into neurotoxic metabolites in the body. No doubt about it. But I absolutely despise this 'explanation.' :)

The problem is that the 'neurotoxic metabolite' theory just replaces the neurotoxic amphetamine you deliberately ingested with another neurotoxic amphetamine that your body formed on its own. That's more of an evasion that an explanation; we already knew that amphetamines (of any sort) tend to be neurotoxic, so it's not actually surprising to find that a (still an amphetamine) metabolite of MDMA is itself neurotoxic.

The other problem I have with this gleeful hunt for a neurotoxic metabolite is that the whole damn line of questioning is based on one old study that injected MDMA into specific parts of the brain of monkeys without producing neurotoxicity. "Well,' they said, "if the drug isn't directly toxic when applied to the brain, then it must be something that's formed elsewhere (a metabolite) doing the damage."

Except we've learned in the years since that overheating is a critical factor in MDMA neurotoxicity; something that those localized injections into the brain rather certainly didn't cause. In other words, viewed through the lens of newer research, there's not actually a good reason to suspect that a toxic metabolite is the sole or primary actor in MDMA neurotoxicity.



My theory remains that MDMA itself is broken down by MAO, creating reactive oxygen species that can (under the right conditions) lead to destruction of the axon.

The funny thing is that nobody seems to have ever closely examined the capacity of MAO to degrade any sort of amphetamine. It's just been assumed since the dawn of pharmacology that it doesn't because amphetamines are orally active (while phenylethylamine is not, since MAO breaks it down too rapidly.)

After all, even if you want to blame a metabolite, you still have to explain how it can create oxidative damage in the axon. Degradation by MAO could explain it.
Click to expand...

This is seriously one of the best posts I've ever seen. Articulation combined with education into WIN.

As largely irrelevant as this post is, after what you said there's nothing I could possibly add, so kudos for the awesome post.
 
I personally wouldn't say the theory involving dopamine breakdown has been disproven. It's just been shown that DA is not essential for MDMA neurotoxicity.
Click to expand...

Ahh, yes, I agree. MAO does break down dopamine, dopamine can get into serotonin axons, and the process would be expected to contribute to oxidative stress. Putting it more precisely, I would say that there is reasonably convincing evidence that dopamine oxidation is not the sole or majority cause of MDMA neurotoxicity. It could certainly still be a contributing factor.
 
Perhaps the MAO degradation of the serotonin itself? Many studies showing that selegiline (an MAOI) greatly reduces MDMA toxicity, in which case anti-oxidants would still help, and perhaps the rest is indeed 5HT2 glutamate excitotoxicity. Either way, I'm looking for a way to reduce toxicity for now, not eliminate it.
 
i hear coke + e is a very common combination

i don't think people would still be doing it if it were that bad ? (just a guess)
 
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