selegiline & MDMA neuroprotection mechanism

[LMM]

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

because you are gay

 

[BilZ0r]

Yeah, I was to see someone make brain microsomes, and see what metabolism they do to MDMA. I bet the brain can metabolism MDMA straight to whatever orthoquinone it needs to. and I was to see someone do an ICV injection, with proper hyperthermia, and then do proper stats.

 

[nuke]

Yeah, I was to see someone make brain microsomes, and see what metabolism they do to MDMA.

You mean, like this (just found it, hah, I should have bothered to check e is for ecstasy again)?

Lin, L., Kumagai, Y., Cho, A.K. Enzymatic and Chemical Demethylenation of (Methylenedioxy)amphetamine and (Methylenedioxy)methamphetamine by Rat Brain Microsomes. Chem Res. Tox. 5 401-406 (1992)

Metabolism of MDA and MDMA by microsomal preparation from rat brains. The products observed were the corresponding catechol derivatives. The oxidizing agents appear to involve both a cytochrome P-450 component and hydroxyl radical.

pdf:
http://scholar.google.com/url?sa=U&...2/5/i03/f-pdf/f_tx00027a013.pdf?sessid=6006l3

And

In vivo formation of aromatic hydroxylated metabolites of 3,4-(methylenedioxy)methamphetamine in the rat: identification by ion trap tandem mass spectrometric (MS/MS and MS/MS/MS) techniques.

Lim HK, Foltz RL.

Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84108.

Aromatic hydroxylation has been established as a pathway for the in vivo metabolism of 3,4-(methylenedioxy)methamphetamine (MDMA) in the rat. Hydroxylation occurred at positions 2, 5 and 6 of the 3,4-methylenedioxyphenyl ring, but is favored at the 6 position. All three regioisomers of both hydroxy-MDMA and hydroxy-3,4-(methylenedioxy)amphetamine (hydroxy-MDA) were detected in the rat liver when 20 mg kg-1 of MDMA was administered. However, 6-hydroxy-MDMA and 6-hydroxy-MDA were the only hydroxylated metabolites detected in the rat brain and plasma and no hydroxylated metabolites were detected in the urine. The hydroxylated metabolites were identified by co-injection of synthetic reference compounds and comparison of the mass spectra of the trifluoroacetyl derivatives of the metabolites with the synthesized reference compounds. The regioisomers of both hydroxy-MDMA and hydroxy-MDA could not be distinguished by either single-stage or two-stage mass analysis. However, employment of a third stage of mass analysis produced distinctly different mass spectra for each of the three regioisomers.

I included a sketch of the metabolism of MDMA to probably toxic compounds in the brain based on this. Well, I guess this makes a fair bit more sense now. Here's a reference about the toxicity of a bunch of the presumable compounds. But why does salicylate not protect against neurotoxicity? And where does MAO-B play a role here? Maybe it doesn't. Selegiline is antioxidative in and of itself, so maybe that's why we don't see neurotoxicity when it is administered.

 

[B9]

So since I am here anyway doing my errands for F & B ! Do you clued up folks reckon I should start gobbling selegiline or just say fuck it ?

Seriously an answer would be nice , yes or no would do and is easier than telling me to read a zillion words !

 

[Ernestrome]

Can be dangerous, so if not prepared to read then best not to. Definitely NOT one for gobbling , esp when mixed with teh MDMA

No offence intended, or allowed to be taken.

Final answer - NO.

 

[nuke]

No, at least, if you intend on using drugs in conjunction with it. Phenethylamine stimulants and MAO-B inhibitors together can cause dangerous rises in body temperature and unpredictable potentiation. Don't do it!

 

[sci-n-tfik]

can anyone help??

what drug can i take that has the same feeling that of ecstasy? and how can i make it? i live in an island so i have a hard time of getting ecstasy. tnx! and peace

 

[bigmac74]

what drug can i take that has the same feeling that of ecstasy? and how can i make it? i live in an island so i have a hard time of getting ecstasy. tnx! and peace

N-hydroxy-MDMA.

 

[B9]

Can be dangerous, so if not prepared to read then best not to. Definitely NOT one for gobbling , esp when mixed with teh MDMA

No offence intended, or allowed to be taken.

Final answer - NO.

No offence intended, or allowed to be taken.

I am heartbroken erne you are cruel of tongue


Can't you lot summarise once you've dissected the minutiae and squabbled about extremely minor irrelevant details such as .gov versus .org ?
Would/could actually get interesting then !


*runs away fearfully, looking behind himself*

 

[nuke]

Some further unraveling:
http://www.ncbi.nlm.nih.gov/entrez/..._uids=16581972&query_hl=2&itool=pubmed_docsum

It seems that prostaglandin H synthase inhibition also reduces neurotoxicity. This enzyme, along with others, is probably responsible for the reduction of MDMA metabolites into quinones (creating oxidative radicals), and so protection gained by the introduction of aspirin (a PHS inhibitor) should be no surpise.

There's an article here about how 2(3)-tert-butyl-4-hydroxyanisole (a phenol) is o-demethylated and peroxidated to para/hydroquinones by PHS, producing radicals, which may elucidate the workings of PHS some.

 

[Ernestrome]

Nuke, did you meant to post that in the aspirin and mdma thread?

Zophen. If you can take no more than 0.5 or 1mg selegiline pre mdma, one should be ok. However if i were doing it, i would be treating it as an experiment, and using a low dose of mdma as well, for safety's sake.

Also need to note that selegiline can build up in the brain, so if you were taking it daily, for neuroprotective purposes (common amongst the elderly ) then you might consider a day or two break, and then a 1mg dose.

In general i believe selegiline isn't widely mentioned as a preload because it is hard to get (prescription in the UK) and the possible dangers inherent in using it.

I have considered it, but decided not to purchase selegiline for this purpose. If i had selegiline, i probably would take it.

 

[nuke]

Nuke, did you meant to post that in the aspirin and mdma thread?

Just forwarding some thoughts from there.

 

[Psychedelics_r_best]

This has all already been said, but I shall give my input. The neurotoxicity of MDMA is thought to be due to oxidative stress. Specifically, dopamine is reabsorbed into serotonin vesicles through reuptake valves. Dopamine is already tocix to these cells, but ontop of that MAO-B reduces the dopamine, realeasing Hydrogen Peroxide, probably from the two hydroxy groups bound to its ring structure. The oxidative stress and hydrogen peroxide cause your axonal serotonin structures to withdraw themselves from the synapse and "srhivel" due to inhibition of the cells ability to generate ATP for energy.

These effects can be prevented by taking anti-oxidative supplements and by taking some SSRI type drug. However, one msut be extremely careful when combing SSRI's and MDMA, because an overwhelming presence of serotonin can cause serotonin syndrome.

http://www.erowid.org/chemicals/mdma/mdma_neurotoxicity1.shtml

 

[nuke]

^^
No, it's already been shown that even if there is no dopamine to be released (by depleting storage vesicals), there is still neurotoxicity present. DA seems to play a role in neurotoxicity mostly through temperature increases. I mentioned this earlier in the thread.

 

[vecktor]

I haven't read it properly but there is a review on neurotoxicity here,

http://www.med.miami.edu/psychiatry/newsletter/documents/Itzhak2.pdf

a scan read indicates that it is possible to block neurotoxicity using NOs inhibitors hyperthermic or not
V

 

[Psychedelics_r_best]

Well then. From what I have newly read, it appears that both temperature and oxidative stress are the major factors. Since the release of dopamine and norepinephrine, coupled with the activites usually done while on MDMA, raise body temperature, your bodies natural defences against oxidative stress become less effective and overwhelmed, producing the neurotoxicity from the oxidative stress (most significantly from an unkown toxin that results from consumption of MDMA.)

And of course temporary neuroadaptive effects such as downregulation of SERTs, low levels of serotonin, and such recorrect themselves after exposure to the drug has ceased. It appears to be though, that from the research presented, the neurtoxic effects are minor enough that they correct themselves in similar time spans as the neuroadaptive effects.

Is that accurate?

 

[nuke]

I haven't read it properly but there is a review on neurotoxicity here,

Thanks for reminding me about that article, I'd seen it before and meant to go over it but had forgotten about it.

Basically, it theorizes how nNOS (neuron nitric oxide systems) lead to dopaminergic neurotoxicity in the brain through the interaction of dopamine, NO, and glutamate systems. nNOS-induced dopaminegic neurotoxicity was prevented by NOS inhibitors irregardless of hypothermic effects of inhibitors, but serotonergic neurotoxicity still seems to remain in place.

And of course temporary neuroadaptive effects such as downregulation of SERTs, low levels of serotonin, and such recorrect themselves after exposure to the drug has ceased. It appears to be though, that from the research presented, the neurtoxic effects are minor enough that they correct themselves in similar time spans as the neuroadaptive effects.

Negative, I'm pretty sure most studies show that with acute, repeated MDMA exposure results in long-term (52 week+) neurotoxicity to DA and SER systems that is irreversible.

 

[B9]

f i had selegiline, i probably would take it.

I wamt some , we (me and a few others) were gonna buy a shitload but everyone kinda sort of forgot about !! Unfortunately!

 

[Psychedelics_r_best]

Negative, I'm pretty sure most studies show that with acute, repeated MDMA exposure results in long-term (52 week+) neurotoxicity to DA and SER systems that is irreversible.

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

That doesnt seem to be what is published here, and this summary seems quite extensive. Of course if used too extensively I would reason permanent damage can occur but it seems to presented here that most "damage" to SERT systems seems to be reversible.

And what do you mean by 52+ week results that are irreversible? If the damage only last approxiamtely 52 weeks then it is reversible, but if it is irreversible than it last forever, opposed to 52+ weeks.

 

[trypt]

And what do you mean by 52+ week results that are irreversible? If the damage only last approxiamtely 52 weeks then it is reversible, but if it is irreversible than it last forever, opposed to 52+ weeks.

I would assume they stopped making observations after 52 weeks and assumed the neurotoxicity was permanent. You have to stop the experiment and publish the results at some point....