MDMA and ampheamne metabolism and neurotoxicity.

[/navarone/]

Good day my fello bluelighters.

As ususal i got a couple of questions regarding the metabolism and the neurotoxicity of some amphetamines.

First:
Wich out of theese 3 amphetamine is the least neurotoxic?

1) Meth 2) MDMA 3 )Phenmetrazine

Second:
I've been recetly studying the way in wich mphetamines and MDMA are metabolized and i still don't understand if it is the molece itself to be neurotoxic or the products resulting from its metabolism.

Let's make an example

MDMA ---(CYp2C6 demethylenation)---> 3,4,-dihydroxymethamphetamine (DHMA)

Wouldn' this reaction give out formaldehyde? What happends to the carbon that used to be bonded to the oxygens?

Then

DHMA ---(N-Demethylation)---> Dihydroxyamphetamine (DHA) + Methanol

Again what happends to the carcon hydrolised fom the amine? will it be oxidised into formaldehyde?

Further on:

DHA ---(COMT)---> 4-hydroxy,3-methoxyamphetamine (HMA)

And to finish:

HMA ---(MAO)--> Homovanillic acid (HVA)

Wich i guess is the last molecule that is later expelled from the body.

From what i can see.....there's a lot of nasty formaldehyde in this metabolic pathway. Could this be a cause for the neurotoxicity of MDMA?

Could someone enlight me on this please?

Thanks

 

[/navarone/]

Forgot one thing.

Is it only the d-methyl group at the alpha carbon responsible for the 'stimulating' effects of amphetamines?

 

[mad_scientist]

I'm pretty sure the neurotoxicity goes

meth > MDMA > phenmetrazine

It looks like the neurotoxicity of MDMA derives from multiple mechanisms, although oxidative stress exacerbated by hyperthermia is probably the primary cause.

The alpha-methyl group mainly seems to inhibit metabolism by MAO, if you take phenethylamine with MAO-inhibitors they have stimulating effects so its more of a general "class effect".

 

[MurphyClox]

Ohoho, stop stop. One thing after another...

1. It's more or less established that the metabolites cause the toxicity and not MDMA itself.
Ref:
as below

2. Consider a 150 mg dose of MDMA, already quite strong. This equals approx. 780 µmol, which is also the amount of formaldehyde that would get released (if it is indeed formaldehyde that gets released). Not to forget: ~780 µmol over a period of several hours! So: Nothing to worry about! That's an amount which our metabolism can handle easily. For my sake, double this number, as we have a second HCHO-"releasing" reaction. Still a minor quantity...
Ref:
Any textbook on organic chemistry and biochemistry.

3. I second Mad_Scientist: There are several toxicity-mechanisms mentioned in the literature, the main one being probably hyperthermia + reactive MDMA-metabolites (in particular the ones with 2 free OH-groups) which cause oxidative stress.
Ref:
J Pharmacol Exp Therap 2006, 316, p.53

4. To my best knowledge, it's the 2D6-isoform and not the 2C6 that demethylenates MDMA to yield 3,4-dihydroxy-meth. To a minor degree 2B6, 1A2 and 3A4 are involved, too.
Ref:
Drug Metabol Dispos 2004, 32, p.1001
J Psychopharmacol 2006, 20(6), p.842

An excellent review about MDMA's pharmacology can be found here: Pharmacol Rev 2003, 55, p.463; the neurotoxicity-issue was extensively reviewed at Erowid (see there for the respective data).

Have a nice day.

Murphy

 

[/navarone/]

Ohoho, stop stop. One thing after another...

1. It's more or less established that the metabolites cause the toxicity and not MDMA itself.
Ref:
as below

2. Consider a 150 mg dose of MDMA, already quite strong. This equals approx. 780 µmol, which is also the amount of formaldehyde that would get released (if it is indeed formaldehyde that gets released). Not to forget: ~780 µmol over a period of several hours! So: Nothing to worry about! That's an amount which our metabolism can handle easily. For my sake, double this number, as we have a second HCHO-"releasing" reaction. Still a minor quantity...
Ref:
Any textbook on organic chemistry and biochemistry.

3. I second Mad_Scientist: There are several toxicity-mechanisms mentioned in the literature, the main one being probably hyperthermia + reactive MDMA-metabolites (in particular the ones with 2 free OH-groups) which cause oxidative stress.
Ref:
J Pharmacol Exp Therap 2006, 316, p.53

4. To my best knowledge, it's the 2D6-isoform and not the 2C6 that demethylenates MDMA to yield 3,4-dihydroxy-meth. To a minor degree 2B6, 1A2 and 3A4 are involved, too.
Ref:
Drug Metabol Dispos 2004, 32, p.1001
J Psychopharmacol 2006, 20(6), p.842

An excellent review about MDMA's pharmacology can be found here: Pharmacol Rev 2003, 55, p.463; the neurotoxicity-issue was extensively reviewed at Erowid (see there for the respective data).

Have a nice day.

Murphy

Either you're a genius or your out of your mind....

Could you explain again your statement in a more compehensible way plz?

BTW why is meth more neurotoxic than MDMA?

 

[/navarone/]

BTW, could it be that the dextro alpha methyl group of amphetamines is resposable for its neurotoxicity?

 

[Lupus]

Non IV amphetamine in sane doses has never proven to be neurotoxic by its self aside from one study by george ricaurte's lab and he is an utterly incompetent fuckwit. I would assume the neurotoxicity occurs from the activation of the SERT cells and then the indirect MAOI action of the amphetamine.

Im also assuming theres no reuptake inhibition at 5-HT receptor sites because that would inhibit the "trippiness" that happens from 5-HT2a activation.

 

[Hammilton]

BTW, could it be that the dextro alpha methyl group of amphetamines is resposable for its neurotoxicity?

No, and you cannot look at one group in the molecule and attribute the ills of a drug with that one little bit. That's not how things work.

PEA + Selegiline (pretending that the latter wasn't neuroprotective) would have the same issues.

All of these stimulants are neurotoxic to some degree.

 

[Hammilton]

Non IV amphetamine in sane doses has never proven to be neurotoxic by its self aside from one study by george ricaurte's lab and he is an utterly incompetent fuckwit(4). I would assume the neurotoxicity occurs from the activation of the SERT cells (1) and then the indirect MAOI action of the amphetamine.(2)

Im also assuming theres no reuptake inhibition at 5-HT receptor sites because that would inhibit the "trippiness" that happens from 5-HT2a activation.(3)

(1) SERT isn't a cell, it's a protein.

(2) If I'm not mistaken, MAOIs are all neuroprotective to some degree.

(3) This doesn't really make sense. You're talking about amphetamine which isn't a SERT ligand and isn't a 5HT2a agonist. No trippiness at all. MDMA IS a SERT ligand, but not an SSRI, it's taken up by SERT and causes mass SE release. I'm assuming in a manner analogous to AMP being taken up by DAT causing DA flood.

(4) There is ample evidence of AMP neurotoxicity. Here's just one study: http://www.acnp.org/G4/GN401000166/CH162.htm You should at least use google before making nonsense claims like that.

 

[MurphyClox]

Either you're a genius or your out of your mind....[1]

Could you explain again your statement in a more compehensible way plz? [2]

[1] For my own sake, I'm hoping for the former...

[2] Which? There are several.

Peace! Murphy

 

[/navarone/]

So from what i undertand, it is not the metbolites of the drug that are neurotoxic but the drug itsell and the stress exerted on the receptor.

The point of my thread was figure out wich out of all amphetamines isthe least neurotoxic.
Of course, the formation of formaldehyde isn't beneficial to the neurons that are being stimulated, but i guess there are other factors that induce neurotoxicity.

Lets make an example: (from a chemical poin of view) why is methampheamine and/ or MDMA neurotoxic?

Mad scientist stated above that MDMA is less neuotoxic than meth, is it because MDMA resembles dopamine and its metabolites more than Meth does or are there other reasons to consider?

BTW how come phenmetrazine is less neurotoxic then other amphetamines.
Is it because of the way it stimulates the dopamine receptor or is it the metabolites to cause neurotoxicity?

Last question: is it possible to synthesise an amphetamine wich doesnt cause neurotoxicity?

 

[MurphyClox]

So from what i undertand, it is not the metbolites of the drug that are neurotoxic but the drug itsell and the stress exerted on the receptor.[1]

The point of my thread was figure out wich out of all amphetamines isthe least neurotoxic.
Of course, the formation of formaldehyde isn't beneficial to the neurons that are being stimulated, but i guess there are other factors that induce neurotoxicity. [2]

Lets make an example: (from a chemical poin of view) why is methampheamine and/ or MDMA neurotoxic? [3]

BTW how come phenmetrazine is less neurotoxic then other amphetamines.
Is it because of the way it stimulates the dopamine receptor or is it the metabolites to cause neurotoxicity? [4]

Last question: is it possible to synthesise an amphetamine wich doesnt cause neurotoxicity? [5]

[1] Considering MDMA, you understood it wrong. I think we can take it as granted that MDMA itself is significantly less toxic than it's metabolites, in particular the ones with 2 free hydroxy-groups. These 2 hydroxys are part of a ortho-quinone-like redox-system and are thought to inflict oxidative stress by reaction with vital cell parts. This is worsened by the MDMA-induced hyperthermia (but the hyperthermia is not the sole cause and must be rather considered in this combination).

[2] Did you read my post? I stated that the released amount of formaldehyde is most probably negligible at the considered doses. It's neither benficial nor dangerous, just irrelevant in this case...

[3] Today is confusion day... Again: MDMA itself is not significantly neurotoxic (except when overdosing heavily or using in long term. but these 'exception' are not what I'm talking about). The 'chemical reason' is in short: An exposed and quite reactive redox-system after a certain metabolic pathway. Meth is a different story (...no other harmful substituents at the phenyl moiety), but this was already covered numerous times here at ADD.

[4] No idea...

[5] Impossible to answer until anybody did so (and proved the lack of toxic effects). To my best knowledge all amphetamine-derivatives are toxic to a certain degree, some less, some more. And of course the same counts like above: This toxicity can (but doesn't have to) be mediated through metabolites.

Peace! Murphy

 

[/navarone/]

[1] Considering MDMA, you understood it wrong. I think we can take it as granted that MDMA itself is significantly less toxic than it's metabolites, in particular the ones with 2 free hydroxy-groups. These 2 hydroxys are part of a ortho-quinone-like redox-system and are thought to inflict oxidative stress by reaction with vital cell parts. This is worsened by the MDMA-induced hyperthermia (but the hyperthermia is not the sole cause and must be rather considered in this combination).

If im not wrong, dopamine adreanline and epnephrine all share the 2 hydroxyl groups..........so according to your statement theese naturally occurring neurotransmittersare neurotoxic?

also....if what u stated above is true, then methamphetamne should be less neurotoxic than MDMA since it doesnt possess the 4,5 OH groups.

 

[MurphyClox]

If im not wrong, dopamine adreanline and epnephrine all share the 2 hydroxyl groups..........so according to your statement theese naturally occurring neurotransmittersare neurotoxic? [1]

also....if what u stated above is true, then methamphetamne should be less neurotoxic than MDMA since it doesnt possess the 4,5 OH groups. [2]

[1] Adrenaline is indeed toxic to a degree, which is one reason (out of several) why it gets metabolized quite fast.

[2] This conclusion is faulty because overall toxicity is not caused by just one reason but rather by the combination of several mechanisms.

I strongly suggest that you get J Pharmacol Exp Therap 2006, 316, p.53 and J Pharmacol Exp Ther 2005, 313, p.422 for a start. Read them and then we talk again... I'm starting to repeat myself.

Peace! Murphy

 

[/navarone/]

i surely will....if i anage to fnd it, im currently studyng biological sciencesandi was aimingat a degree inneurobiology.

my dream would be to discover stimulant/nootropic wich isnt neurotoxc nor harmfu to your body.

BTW the other day iwas readng an article about neurogenesis, to my dissapointment it didnt state any substance able to activate neurogenesis.
Are there any pharms than can stimulate neurogenesis?

 

[kaskelot]

i surely will....if i anage to fnd it, im currently studyng biological sciencesandi was aimingat a degree inneurobiology.

my dream would be to discover stimulant/nootropic wich isnt neurotoxc nor harmfu to your body.

BTW the other day iwas readng an article about neurogenesis, to my dissapointment it didnt state any substance able to activate neurogenesis.
Are there any pharms than can stimulate neurogenesis?

Well, pipradrol and desoxypipradrol isn't neurotoxic or physiologically harmful as far as I know. I'd be pleased to be corrected if I'm wrong.

Cannabinoids does cause some neurogenesis, I've seen it stated here in ADD and if my memory serves as well as it claims there were also some references. That Rimonabant over time causes neurodegenerative problems sort of proves that cannabinoids have at least neuroprotective effects.

Edit: Corrected grammar.

 

[<pyridinyl_30>]

I think it's an interesting fact that 4-hydroxy-3-methoxyamphetamine is a common metabolite of both MDA and amphetamine.

 

[/navarone/]

u meant both "MDMA and MDA"

From what i know, the phenyl group of amphetamine doesnt chanche into a dopamine-like substance.

Maybe tyrosine hydroxylase could interct with the molecule but from what i know amphetamine is oxidised by MAOa to Phenylacetal, and kater on to phenylacetone.