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I Like to Draw Pictures of Random Molecules

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Honestly, you got me, I pulled that out of my ass.
There's been discussion on 5-IT before.

I don't think that MDMA, MDA, and methamphetamine are the *only* stimulants that are neurotoxic if abused.

But honestly the evidence, to me, seems to suggest MDMA's toxicity is something that can be easily migitated by not acting like a 14 year old when it comes to dosing. In single bolus doses of 100-180mg, or even with a single half-size "boster" a few hours in, there's basically no reason to worry about monoaminergic toxicity in a well-fed and watered individual who isn't overheating in a club. With this in mind drugs like IAP et cetera that are reported as "rougher" than MDMA don't seem to me like less toxic substitutes...

There are papers that show methylone is not cytotoxic until combined with methamphetamine. Not sure what the implication of that is.

all I know is amphetamines are unlikely to be "potent non neurotoxic serotonin releasing agents". amphetamine type euphoriants are generally toxic at some level. and I would rather be telling people to be cautious rather than assuming it's non-toxic because there's been no reports of toxicity posted here.

some people use 4-bromo-methcathinone. would I touch it? not with a fucking barge pole.
 
I think its well established that the selective serotonergic toxicity of MDMA/MDA is due to metabolisation into an alpha-methyldopamine analogue: http://www.ncbi.nlm.nih.gov/pubmed/9128836

This explains why co-administration of MDAI with d-AMP showed toxicity and why users feel a worse hangover when combining MDMA and Amphetamine.
 
[MDxx's metabolism to bis-glutathionyl-alpha-methyl-dopamine] explains how [...] MDAI with d-AMP showed toxicity
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I don't follow. Neither amphetamine nor MDAI have a metabolic pathway to a-methyldopamine. (I can see the methylenedioxy ring busting open, but ring-hydroxylation of amphetamine is 10 to 50 times harder to do metabolically.)

I was under the impression that a wide variety of factors contributed to the so-called toxicity of MDMA. Namely, strong multi-monoamine release activity causing oxidative stress and elevation of body temperature. The massive monoamine release seems to be the biggest player in causing shitty after effects.

How do you account for the toxicity of amphetamine (at high doses) and methamphetamine, on their own, then? I don't think the human liver will hydroxylate amphetamine in the 3' position. It will do the 4'position and make alpha methyl tyramine/4-hydroxyamphetamine but I don't think it will take it all the way to a-methyl-dopamine. And dopamine sure as shit won't get alpha-methylated.

I do know the *really* toxic amphetamines like 4-chloroamphetamine, 4-methylthioamphetamine, etc. are very powerful monoamine releasers. Some of them are MAOI's too. Maybe the real mark of toxicity is just a low EC50 for monoamine release. (But also, mephedrone is apparently not toxic to brain cells, and that's a powerful releaser.)

TL;DR: I don't know left from right. Please punch me in the face in front of my church friends.
 
Ditto. The "alpha methyl dopamine" metabolite is just a piece of the puzzle, as the literature currently agrees. Not the sole factor!
 
Even if, however it got there in the first place, alpha methyl dopamine was present, HOW would it be neurotoxic... taking into account dopamine itself is a catelcholamine and it functions at the dopamine receptors wouldnt its a-methly counterpart just provide a stronger attachment to the receptor or am i way off. I cant see how alpha methly dopamine is any more toxic than dopamine taking into account dopamine can oxidise into hydrogen peroxide from the hydroxyl bonds? How dose alpha methylation affect that?

Is it proven that alpha methly dopamine is even a HUMAN metabolite of MDMA? IIRC, it is in rat studies a metabolite? Im a firm believer that breakdown of dopamine into hydrogen peroxide occuring in serotonin neurons is the primary cause of serotonergic neurotixicty thus throwing amphetamine or any dopamine-releaser into the mix with MDMA or any other serotonin releasing drug causes drastically increases neurotoxicity.
 
EDIT: then why do other triple releasers not cause toxicity. Why does dopamine not cause serotonergic toxicity on its own?

Well if you read the study the dual hydroxylation isn't important, just a Hydroxy group for glutathione to bond to. So anything with an amphetamine backbone without ring substitutions is sufficient. This is coupled with the action of a serotonin releaser to induce transporter phosphorylation allows this new chemical to flow down the concentration gradient and into serotonin neurones where presumably MAO-B is involved in some way, then an unknown leap to oxygen radicals. My speculation is that it inactivates endogenous antioxidants through some mechanism allowing dopamine to be oxidised.

The clincher is the fact that injecting said metabolite directly into neural tissue still yields selective serotonergic toxicity, while injecting pure mdma does not (liver enzymes demethylate MDMA).
 
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Methamphetamine is toxic to Dopaninergic neurones mostly:www.aapsj.org/view.asp?art=aapsj080248

P-CA haven't been studied well enough to truley be claimed as neurotoxins in humans. 4-FA appears to be harmless and in the shulgin index shulgin references 2 studies claiming 4-CA was used in human trials for a year without ill effects.

I remember reading somewhere (but I can't remember where so take this as hearsay) that rather than being neurotoxic 4-CA merely induced SERT downregulation for 24 hours but levels returned to normal after. During this time however it would appear to havecaused serious neurotoxicity.
 
Several ideas that have probably been brought up in this thread, can't draw them though so I will explain in best of detail. on phone, tired but with ideas need to write down

Firstly, NBOMes. With a halogen substituent on the nbome. I don't know about positions in terms of activity so come up with the best. Will this work or just silly?

1b. Other varying substituents on the Benzyl, essentially to the point of symmetry

2. NPOMes - Phenyl instead of benzyl

3. 6-ethylamine tryptamine. PEA one way, TRYP the other.
4. As above but without tryps ethylamine so a PEA with NHCH2 on the ring. Indole and done before?

5. alpha aminating a PEA. I'd guess inactive/metabolised quickly

6. 2/3/4/3,4 hydroxy AMPs. Neurotoxic I guess?

I like peas, theyre easy to draw.

E: Yes 4 is pretty much 5-API/5-IT
 
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Thiophene Based Phenethylamine Psychedelics

Okay, so looking at MPA, thinking about drugs like MDMA and 5/6-APB made think, why couldn't there be phenethylamine psychedelics with a thiophene ring? The sulfur at the top could act as an oxygen and you would only need the proper substituents at the 4 and 5 position. Probably won't work for a variety of reasons, but I figured I'd ask anyway.

Methiopropamine for an example: http://en.wikipedia.org/wiki/Methiopropamine
 
Maybe it's possible, there are still a lot of chemicals that haven't been tested for their effects or even synthesized.
 
The sulfur at the top could act as an oxygen
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that's not how it really works; thiophene is aromatic and the sulfur is not as reactive as a "normal" one. the thophenyl group is a bioisostere for phenyl.

you could still have substituted thiophenylethylamines though.
 
sekio said:
that's not how it really works; thiophene is aromatic and the sulfur is not as reactive as a "normal" one. the thophenyl group is a bioisostere for phenyl.

you could still have substituted thiophenylethylamines though.
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So the sulfur would in no way replace the methoxy that is normally at the 2 position on psychedelic phenethylamines?

I don't think any drugs with this substitution would be that great but who knows.
 
Thank you for the knowledge. From what I got from all of that, my idea would be plausible but not the way I said it. Thiophenethylamine psychedelics seem like a real possibility however.
 
here's an under-explored family of sulfur containing phenethylamine psychedelics that imo actually looks pretty promising:

http://en.wikipedia.org/wiki/TOM_(psychedelic)
http://en.wikipedia.org/wiki/TOET_(psychedelic)

740px-2-TOM.png
 
5-TOM and 5-TOET sound awesome, just like I expected for some reason... I've actually looked at these molecules before in Pihkal and would be interested in getting some of them synthesized for science! 5-TOET sounds amazing.
 
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