selegiline & MDMA neuroprotection mechanism

[specialspack]

According to Nichols etc:

http://mdma.net/depsave.htm

selegiline produced neuroprotection in rats given MDMA. Since the suggested model of MDMA neurotoxicity is now that heat is the crucial factor, not the presence of dopamine, what would be the mechanism for selegiline's neuroprotection?

Wouldn't increased dopamine levels also promote temperature increase, leading to more neurotoxicity rather than less?

 

[nuke]

The current theories of MDMA neurotoxicity are (as far as I understand) that dopamine enters into promiscuous SERT destroying terminals (via oxidation?) and thioether metabolites of MDMA created by the liver cause oxidative damage. There are a lot of new articles talking about this from 2000-2006 on that same website, check them out. Temperature exacerbates these problems but isn't the direct cause of neurotoxicity. I think the way selegeline prevents neurotoxicity will show itself in the future, but is for the moment unknown (aside from that, I don't think it's a viable means of preventing neurotoxicity, as it causes dangerous body temperature hikes). Perhaps the metabolism of the thioether things into something dangerous occurs by MAO-B.

 

[specialspack]

According to the thedea.org:

http://thedea.org/neurotoxicity.html#m

Dopamine has been ruled out as the cause of neurotoxicity, and I've seen Bilz0r repeat this too... (shame he ain't around!). Temperature now seems to be the main causal factor.

EDIT: Here he is -

Your view on MDMA-mediated neurotoxicity is a bit 1998. The whole dopamine into the serotonin neurons is a bit unlikely... it's something I'm begining to doubt happens even a little bit now.

http://www.bluelight.ru/vb/showthread.php?t=200264

 

[LMM]

According to the thedea.org:

http://thedea.org/neurotoxicity.html#m

Dopamine has been ruled out as the cause of neurotoxicity, and I've seen Bilz0r repeat this too... (shame he ain't around!). Temperature now seems to be the main causal factor.

EDIT: Here he is -



http://www.bluelight.ru/vb/showthread.php?t=200264

Why the fuck are you talking about DEA you faggot narc?

 

[Jamshyd]

Well, aren't MAO enzymes the ones which create free-radicals out of catecholamines in the process of breaking them down? Maybe by inhibiting MAO, you are causing less turnout of free-radicals.

Then again this is just an idea that occured to me - could very well be wrong...

 

[Ernestrome]

Why the fuck are you talking about DEA you faggot narc?

Click the link you feisty greenlighter, and note that is it theDEA.org NOT dea.gov!

 

[nuke]

TheDEA.org's explanation is outdated and there's new evidence against some of the statements the site makes about neurotoxicity. I'd pull some refs but I'm sleepy, maybe tomorrow.

Well, aren't MAO enzymes the ones which create free-radicals out of catecholamines in the process of breaking them down? Maybe by inhibiting MAO, you are causing less turnout of free-radicals.

That's what I'd been thinking.

 

[specialspack]

Well, aren't MAO enzymes the ones which create free-radicals out of catecholamines in the process of breaking them down? Maybe by inhibiting MAO, you are causing less turnout of free-radicals.

Then again this is just an idea that occured to me - could very well be wrong...

Yes, that seems to be the suggestion...

Nuke, love to see those refs when you've got time.

LMM, I'm not going to even dignify that with an answer.

 

[nuke]

Okay, good morning.

It's well known that MDMA is non-neurotoxic if doesn't enter the blood stream (if it's injected in the brain). This seems to indicate that MDMA itself is not neurotoxic, but rather one or more of its metabolites is.

Just recently we've isolated what these metabolites seem to be, and established that they are indeed neurotoxic and able to cross the BBB.
http://www.mdma.net/toxicity/toxmetab.html
http://www.mdma.net/toxicity/toxicmetab.html
http://www.mdma.net/toxicity/thioether-metabolites.html
http://www.mdma.net/toxicity/quinolthioetherconj.html

So, why does selegiline work, and further, fluoxetine (both as previously stated by Nichols), in the prevention of neurotoxicity? Selegiline may prevent dopamine and/or toxic metabolites that's been taken into serotonergic neurons from being futher metabolised by MAO-B, causing oxidative damage. What fluoxetine probably does is keep dopamine/toxic metabolites from entering serotonergic neurons by inhibiting SERT in the first place, thus preventing neurotoxicity. This has been suggested before, neglecting the thioether metabolites.

So it would seem that temperature only plays an exacerbatory role and not a causal one, in any case..

 

[specialspack]

Thanks.. I've heard the toxic metabolites theory before, and again seems plausible. What about the study quoted by thedea.org that shows rats without dopamine undergoing as much neurotoxicity as those without? Has that been repeated and found to not be the case in other studies?

 

[nuke]

Thanks.. I've heard the toxic metabolites theory before, and again seems plausible. What about the study quoted by thedea.org that shows rats without dopamine undergoing as much neurotoxicity as those without? Has that been repeated and found to not be the case in other studies?

I think all that mostly says is that neurotoxicity can be prevented by inducing hypothermia, and that dopamine only minorly runs the toxic show, if at all, probably by increasing body temperature (keep in mind the study did find that MDMA+Reserpine did slightly reduce neurotoxicity, at room temperature). On other studies, from the paper:

The present findings are seemingly in contrast to those by
Stone et al. (1988) and Schmidt et al. (1990b), who found
that reserpine provided some protection from MDMA-
induced 5-HT neurotoxicity. However, those studies were
conducted before the role of core temperature on the
neurotoxic effects of amphetamines was fully appreciated,
and therefore did not control for potential thermoregulatory
confounds. As illustrated in Fig. 10, it is likely that in both of
the aforementioned studies, the hypothermic actions of
reserpine were the source of its neuroprotective actions,
rather than its monoaminergic-depleting effect. In particular,
the timing of MDMA administration relative to that of
reserpine in those studies was such that hypothermic effects
of reserpine were still present. In contrast, Hekmatpanah
et al. (1989) gave MDMA 24 h following reserpine admin-
istration, when hypothermia had largely dissipated. Their
study, like ours, showed that when the hypothermic effects of
reserpine are not present, it fails to prevent MDMA-induced
5-HT neurotoxicity.

So with this in mind, we know the following:
a.) Dopamine plays a minor role in neurotoxicity, if at all.
b.) Toxic metabolites probably play a much bigger role.
c.) Hyperthermia worsens and hypothermia attenuates neurotoxicity.
d.) MAO-B and SERT inhibitors prevent neurotoxicity.
e.) Bypassing the bloodstream prevents neurotoxicity.

Here's my guess to what's going on:
MAO-A metabolises NE and SER, while MAO-B goes for phenethylamines/benzylamines. Whatever causes neurotoxicity seems to necessitate the use of serotonin transporters and also MAO-B; since it's not dopamine going into SERT and screwing things up, something else must be, and the metabolic oxidation of this something else must assumably happen by MAO-B. This points directly to a toxic metabolite formed outside the brain as the cause of neurotoxicity, since the introduction of MDMA directly into the brain will not cause neurotoxicity.

Now, what does the temperature have to do with this? Elevated temperatures lend to increased oxidative stress on the body and brain, and since MDMA induced neurotoxicity seems to be caused by oxidants, this makes sense.

Take this study from Portugal:

The hyperthermic response elicited by MDMA was clearly dose-related and potentiated by high AT (Ambient Temperature). Administration of MDMA produced some evidence of oxidative stress, expressed as GSH depletion at both ATs studied, as well as by lipid peroxidation and decreased catalase activity at high AT. High AT, by itself, decreased glutathione peroxidase activity. Histological examination of the liver revealed abnormalities of a dose-and AT-dependent nature. These changes included vacuolation of the hepatocytes, presence of blood clots and loss of typical hepatic cord organisation. The results obtained in the present study suggest that oxidative stress plays a part in the first stage of MDMA-induced liver damage and that liver antioxidant status is aggravated by increased AT. Thus, these findings are in accordance with the hypothesis that high AT may potentiate ecstasy-induced hepatotoxicity by increasing body hyperthermia.

http://cat.inist.fr/?aModele=afficheN&cpsidt=13629270

This shows something oxidatively problematic occuring in the liver; once again, the finger seems to point to a toxic metabolic product as being the culprit.

 

[bigmac74]

I think all that mostly says is that neurotoxicity can be prevented by inducing hypothermia, and that dopamine only minorly runs the toxic show, if at all, probably by increasing body temperature (keep in mind the study did find that MDMA+Reserpine did slightly reduce neurotoxicity, at room temperature). On other studies, from the paper:

So with this in mind, we know the following:
a.) Dopamine plays a minor role in neurotoxicity, if at all.
b.) Toxic metabolites probably play a much bigger role.
c.) Hyperthermia worsens and hypothermia attenuates neurotoxicity.
d.) MAO-B and SERT inhibitors prevent neurotoxicity.
e.) Bypassing the bloodstream prevents neurotoxicity.

Here's my guess to what's going on:
MAO-A metabolises NE and SER, while MAO-B goes for phenethylamines/benzylamines. Whatever causes neurotoxicity seems to necessitate the use of serotonin transporters and also MAO-B; since it's not dopamine going into SERT and screwing things up, something else must be, and the metabolic oxidation of this something else must assumably happen by MAO-B. This points directly to a toxic metabolite formed outside the brain as the cause of neurotoxicity, since the introduction of MDMA directly into the brain will not cause neurotoxicity.

Now, what does the temperature have to do with this? Elevated temperatures lend to increased oxidative stress on the body and brain, and since MDMA induced neurotoxicity seems to be caused by oxidants, this makes sense.

Take this study from Portugal:

http://cat.inist.fr/?aModele=afficheN&cpsidt=13629270

This shows something oxidatively problematic occuring in the liver; once again, the finger seems to point to a toxic metabolic product as being the culprit.

We should remember that many analogues of MDMA are non-neurotoxic, but remain very similar in chemical structure, such as the 2-aminoindan analogue, the 2-aminotetraline analogue, also, I think the alpha-ethyl and the N-ethyl analogues were said to be non-neurotoxic. The theory for this was "due to lack of DAT activity" IIRC, so it's either a fairly big coincidence, or something deeper, but dopamine definitely has some sort of involvement, however small or obscure.

 

[nuke]

We should remember that many analogues of MDMA are non-neurotoxic, but remain very similar in chemical structure, such as the 2-aminoindan analogue, the 2-aminotetraline analogue, also, I think the alpha-ethyl and the N-ethyl analogues were said to be non-neurotoxic. The theory for this was "due to lack of DAT activity" IIRC, so it's either a fairly big coincidence, or something deeper, but dopamine definitely has some sort of involvement, however small or obscure.

Both MDEA and MBDB are neurotoxic, but less so than MDMA based on potency (but both require higher doses). I'd bet the metabolism of MDAI compound is very different from that of MDMA. The aminoindan structure seems to remove neurotoxicity from even heavily neurotoxic compounds like para-iodoamphetamine. So far there isn't enough research to be sure the exact reason why the aminoindans are not neurotoxic as far as I know, but I'd guess it's somewhere in its metabolism rather than lack of DA affinity.

 

[bigmac74]

Both MDEA and MBDB are neurotoxic, but less so than MDMA based on potency (but both require higher doses). I'd bet the metabolism of MDAI compound is very different from that of MDMA. The aminoindan structure seems to remove neurotoxicity from even heavily neurotoxic compounds like para-iodoamphetamine. So far there isn't enough research to be sure the exact reason why the aminoindans are not neurotoxic as far as I know, but I'd guess it's somewhere in its metabolism rather than lack of DA affinity.

Okay thanks, I must have been getting something mixed up when I thought that the N-ethyl / alpha-ethyl analogues were non-neurotoxic.

 

[vecktor]

Okay thanks, I must have been getting something mixed up when I thought that the N-ethyl / alpha-ethyl analogues were non-neurotoxic.

Anything is neurotoxic at a high enough dose. for example there is some evidence that DOI a pure 5ht2a/c agonist is neurotoxic at plasma levels around 10 to 100x recreational levels, and its neurotoxic action is strikingly similar to MDMA's.
the question then arises, does mixing a 5ht2a/c agonist with MDMA increase the neurotoxic action, or lower the dose threshold for significant neurotoxicity?

 

[nuke]

Anything is neurotoxic at a high enough dose. for example there is some evidence that DOI a pure 5ht2a/c agonist is neurotoxic at plasma levels around 10 to 100x recreational levels, and its neurotoxic action is strikingly similar to MDMA's.
the question then arises, does mixing a 5ht2a/c agonist with MDMA increase the neurotoxic action, or lower the dose threshold for significant neurotoxicity?

That DOI study is another interesting piece to add to the puzzle, I'd almost forgotten about it. If I remember right, DOI barely binds to dopamine, so again it seems dopamine isn't too important for neurotoxicity. LSD has a some minor dopaminergic activity in very large doses, and doesn't seem to cause any sort of serotonergic terminal or T-hydroxylase damage.

My thoughts here is that the metabolism of amphetamines is key to serotonergic/dopaminergic neurotoxicity. I haven't heard of a phenethylamine psychedelic ever causing neurotoxicity, but there are countless examples of amphetamines yielding it. When studies come back about the metabolism and neurotoxicity of compounds like MDPV and Phenyl-PV, it might become more clear. My personal guess is that neither compounds will be very neurotoxic, if at all (these are both alpha-propyl-PEAs with low active doses).

the question then arises, does mixing a 5ht2a/c agonist with MDMA increase the neurotoxic action, or lower the dose threshold for significant neurotoxicity?

My personal guess is that since 5HT2A/C agonism leads to an increase in temperature, there will be an increase in oxidative free radical and thus an increase in neurotoxicity. MDA has a greater impact on 5HT2A/C and is roughly three-fold as neurotoxic as MDMA. Further, reducing the body temperature of rats who are then administered MDMA in turn reduces neurotoxicity. Perhaps Meth-amp's dramatically toxic neurological effects spawn from its effects on serotonin, too. Here is a study where reductions in body temperature reduced the dopaminergic neurotoxicity of meth-amp.

 

[BilZ0r]

I would ignore the DOI study. If mememory servers it was in cortical neural culture. Wrong neurons. They tested cell explosion with an LDH assay. Wrong test. MDMA was only neurotoxic in these conditions at 100s of micromolar. Wrong concentration.

Just ignore it.

 

[nuke]

^^ Okay, thanks for that info

 

[TheDEA.org]

TheDEA.org's explanation is outdated and there's new evidence against some of the statements the site makes about neurotoxicity.

I'd be happy to hear your criticisms. If there's even credible doubt about something on my site, I'll take it down or qualify it.

e.) Bypassing the bloodstream prevents neurotoxicity.

There's no evidence of that. Oh, you mean the direct injection into the brain experiment?

You're ignoring the confound of body temperature. MDMA neurotoxicity is largely a function of elevated body temperature, most likely due in part to metabolic impairment leading to membrane depolarization, inducing nitric oxide synthase (in my outdated opinion, of course. Localized injections into the brain are very unlikely to cause the sort of core body temp increases seen from systemic administration. But, the silly people have just gone chasing off after this red herring for years, never looking back, never bothering to wonder if the data actually supported the conclusions. (Data rarely lies, but people fuck up the interpretation all the time. For instance, Nichol's 'dopamine toxicity' conclusions have been disproven, but his data is still interesting and useful.)

That one highly suspect study is essentially the entire basis of the enthusiasm for the 'toxic metabolite' theory. Neurotoxicity is a very common (if not universal) quality of amphetamines. That a novel amphetamine produced in the liver from a known amphetamine is still neurotoxic doesn't even merit a raised eyebrow, yet they swing that dead cat around by the tail as if they have cracked the case.


Oh, If only we could find a molecule that is dependent on the SERT to enter the serotonin axon! Like MDMA is. If only we could find a molecule that has a significant affinity for MAO-B. Like MDMA does. If only we could find a molecule that is attacked at the amine within brain tissue. Like MDMA is. Boy, there just aren't any good candidates. Yes, I know. MAO doesn't attack amphetamines. Everybody knows that. And that's the problem; conventional wisdom has become unassailable dogma.

Consider the problem: What could stop MAO from attacking an amphetamine when phenethylamine is an ideal substrate? Well, there are always steric problems; change the shape/size and you may no longer get a significant retention of the substrate or proper positioning against the catalytic group. But adding an alpha-methyl, N-methyl isn't much of a change, and we know experimentally that MDMA still has a significant affinity for MAO. The other problem is changes in electron density; for instance, chlorinate a hydrocarbon and it becomes harder to further oxidize. Yet, MAO rips through the tertiary amine of DMT as if it were nothing, so both the steric and electron donating/withdrawing effects of a couple methyl groups probably aren't an absolute barrier.

So, can MAO metabolize amphetamines? Not only will I say that it might be possible, I would go so far as to say that it almost certainly MUST be possible.

The 'dopamine toxicity' theory was in some ways elegant, but it's deader than the dodo. The 'toxic metabolite' theory is little more than a sideways dodge that doesn't begin to explain the 'why' of amphetamine axon pruning. The evidence of a profoundly important role for MAO is almost beyond debate, and there's just no good reason why a metabolite of MDMA (altered at the ether ring) should be much more or less vulnerable to MAO at the amine than MDMA itself.


Or so it seems to me.

What's your take on it?

 

[nuke]

I'd be happy to hear your criticisms. If there's even credible doubt about something on my site, I'll take it down or qualify it.



There's no evidence of that. Oh, you mean the direct injection into the brain experiment?

You're ignoring the confound of body temperature. MDMA neurotoxicity is largely a function of elevated body temperature, most likely due in part to metabolic impairment leading to membrane depolarization, inducing nitric oxide synthase (in my outdated opinion, of course. Localized injections into the brain are very unlikely to cause the sort of core body temp increases seen from systemic administration. But, the silly people have just gone chasing off after this red herring for years, never looking back, never bothering to wonder if the data actually supported the conclusions. (Data rarely lies, but people fuck up the interpretation all the time. For instance, Nichol's 'dopamine toxicity' conclusions have been disproven, but his data is still interesting and useful.)

That one highly suspect study is essentially the entire basis of the enthusiasm for the 'toxic metabolite' theory. Neurotoxicity is a very common (if not universal) quality of amphetamines. That a novel amphetamine produced in the liver from a known amphetamine is still neurotoxic doesn't even merit a raised eyebrow, yet they swing that dead cat around by the tail as if they have cracked the case.


Oh, If only we could find a molecule that is dependent on the SERT to enter the serotonin axon! Like MDMA is. If only we could find a molecule that has a significant affinity for MAO-B. Like MDMA does. If only we could find a molecule that is attacked at the amine within brain tissue. Like MDMA is. Boy, there just aren't any good candidates. Yes, I know. MAO doesn't attack amphetamines. Everybody knows that. And that's the problem; conventional wisdom has become unassailable dogma.

Consider the problem: What could stop MAO from attacking an amphetamine when phenethylamine is an ideal substrate? Well, there are always steric problems; change the shape/size and you may no longer get a significant retention of the substrate or proper positioning against the catalytic group. But adding an alpha-methyl, N-methyl isn't much of a change, and we know experimentally that MDMA still has a significant affinity for MAO. The other problem is changes in electron density; for instance, chlorinate a hydrocarbon and it becomes harder to further oxidize. Yet, MAO rips through the tertiary amine of DMT as if it were nothing, so both the steric and electron donating/withdrawing effects of a couple methyl groups probably aren't an absolute barrier.

Well, the role of MAO-B has so far been shown to be essential to toxicity. But what has not been shown is that MDMA has been metabolised by MAO-B, despite being a substrate for it. I think it's just as possible, if not moreso, that a toxic metabolite such as alpha-methyldopamine or alpha,n-dimethyldopamine (both urinary metabolites of MDMA) be responsible for a lot of this damage. These should be oxidatively reduced to ortho-quionones, as well as its variously para-substituted comrads, and 6-OH-DA is certainly neurotoxic enough (with MAO-B inhibition yet again preventing 6-OH-DA neurotoxicity). Amphetamine is still neurotoxic depite lacking the n-methyl while n-methyl-phenethylamine is not (in fact, the n-methyl is probably very easily knocked off in the brain), and that is why I think that de-amination of MDMA not be crucial to any sort of neurotoxicity, if involved at all. If MDMA was n-de-aminated like NMPEA is by MAO, knocking off a methylamine and I'd guess leaving 3,4-methylenedioxyphenyl-2-propanol, the metabolic products of MDA might be neuroprotective like 3,4-dihydroxyphenylethanol, a dopamine metabolite, and we wouldn't be having this conversation. But I have a good feeling that the alpha-methyl part of MDMA prevents this from happening. This is also presumably why PEA, NMPEA, and MDPEA is very not active.

MAO in general is promiscuous, but to what extent is not known. The important part about DMT is that the extended methylation happens on the amine rather than the preceding alkyl chain. All the of the alpha-methylated tryptamine psychedelics listed in TiHKAL are active psychopharmaceutically. Perhaps, as has been the age-old theory, the activity of such phenethylamine and tryptamine psychedelics depends specifically on the slow metabolism of the liver and inability to be broken down by MAO in the body and brain, and alpha-methylation seems to do just that.

So, can MAO metabolize amphetamines? Not only will I say that it might be possible, I would go so far as to say that it almost certainly MUST be possible.

Why must it be possible? The liver has surely shown its worth in the metabolism of various amphetamines.

The 'dopamine toxicity' theory was in some ways elegant, but it's deader than the dodo. The 'toxic metabolite' theory is little more than a sideways dodge that doesn't begin to explain the 'why' of amphetamine axon pruning. The evidence of a profoundly important role for MAO is almost beyond debate, and there's just no good reason why a metabolite of MDMA (altered at the ether ring) should be much more or less vulnerable to MAO at the amine than MDMA itself.

There's also no good reason to believe that MDMA is metabolised by MAO-B, as far as I can tell, until there is proof that it indeed does. It's perfectly possible that it does, in turn yielding neurotoxicity, but we won't know until some clever person or group of people decides to run tests of intrastriatal administration of MDMA at variable temperatures.