Mephedrone - What do we know?

[bluedolphin]

MDPV feels highly selective for dopamine but there must be a saturation point... because with higher and repeated doses it becomes very empathogenic and entactogenic. Saturation of dopamine receptors > crossover to Sert?

 

[Hammilton]

Yes it was rather confusing as there are a number of drugs that are very selective DARIs, it would have been much easier to simply say MDPV in that it referenced a specific compound. Also as muphy pointed out there is no real conclusive evidence as to which DARI is most selective as far as I am aware of. But lets not get too off topic.

You're still not getting it. I was referring to a hypothetical group of selective DARIs with no non DA effects.

God, you try making a joke and spend 90% of the time explaining it.

I don't know that Murphy said such a thing, but indeed, I doubt there has ever been research to see what is the most selective DA reuptake inhibitor.

 

[slopoke]

Thats what you get for telling shit jokes.

 

[Hammilton]

No kidding.

 

[pofacedhoe]

yeah its not my stupid fault you think that implausible concepts are funny-i think they may be plausible which leads to confusion


joke

whats fat and dangerous- praying mantits!

 

[vortex30]

/thread

Someone bump when we actually know something and don't have to start talking about MDPV and the SS DARI.

 

[pofacedhoe]

i know i had a couple of lines today and my jaw is gringing like mad.

 

[vortex30]

i know i had a couple of lines today and my jaw is gringing like mad.

Yeah, I decided drunk as fuck to have a few lines and now my mouth/jaw is in quite the funny position. But for ADD...Ohhhh Bruxia OMG! I'm fucksed.

 

[Hammilton]

yeah its not my stupid fault you think that implausible concepts are funny-i think they may be plausible which leads to confusion

Actually, it kind of is. Why exactly is a dopamine reuptake inhibitor that's highly selective implausible? Amfonelic acid has virtually no effect on NE levels. It does apparently increase 5HT levels by blocking the efflux of 5-HIAA, which probenecid also does. It does not appear to be relevant for recreational use, though.

A stupid play on words. Super selective dopamine reuptake inhibitor becoming SSDARI or SS DARI, the latter said as an acronym and you've got "SS Dairy" (phonetically spelled so you wouldn't be further confused), which sounds like the name of a boat, many of which are given SS (sailing ship, or steam ship) before a name. DARIs are stimulants, if you didn't know: hence the 'fastest boat in the fleet' comment.

What would happen if I actually said something factually wrong? I mean, shit, I do, frequently even. You'd think that something obviously on-topic but wrong would confuse you much more than a stupid word play that used about 50 characters- including spaces- might have such power to disrupt your world.

I mean, I know I'm a genius and all, but this is all too much. First I'm compared to House, now I learn that 50 characters can confuse everything you know about pharmacology. If that's not ego-inflating, I dunno what is.

Someone bump when we actually know something and don't have to start talking about MDPV and the SS DARI.

You already have your answer: It has not been studied. If you're just looking for useless anecdotal information, read the trip reports. However, if you want useful research, you're not going to get it because it just hasn't been done. Probably will be, but as of today, there's nothing. You can't get what doesn't exist yet.

There's already good conjecture here, and it's probably even right, but no one knows.

 

[Rectify]

What makes you think you're a genius?

 

[vortex30]

First I'm compared to House, now I learn that 50 characters can confuse everything you know about pharmacology.

OMG OMG There was a new episode yesterday I think!!!! I'm on Meph, yippee lol. Thanks for the reminder, eh?

 

[fireball]

Hello, new here.

I found nothing at NMDA and very weak inhibition of ACh. Is it worth me seeing if i can find 5-HT2b or DA clones or is the purity of my sample going to mean the results will be pointless anyway? I made the mistake of believing the label therefore what i thought was my 10 mM solution could be anything.

 

[vecktor]

Hello, new here.

I found nothing at NMDA and very weak inhibition of ACh. Is it worth me seeing if i can find 5-HT2b or DA clones or is the purity of my sample going to mean the results will be pointless anyway? I made the mistake of believing the label therefore what i thought was my 10 mM solution could be anything.

interesting, I guess you will want to look at the monamine transporters DAT NERT SERT and VMAT 2

 

[bpayne]

I love house man, great fucking show!

 

[nuke]

This is a post from the other mephedrone thread, but it should probably be here too:

You don't even need to justify it by saying that it's a metabolite -- it's well know that putting a hydrophobic atom into the 4-position increases an amphetamine's affinity for SERT and thus serotonin release, which is well known to be a precursor for amphetaminergic neurotoxicity and cardiotoxicity.

EC50 DA/NE/5HT nM

d-Amphetamine 8.0±0.43, 7.2 ±0.44, 1756±94
meta-Methylamphetamine 33.3±1.3, 18.3±1.4, 218±22
para-Methylamphetamine 44.1±2.6, 22.2±1.3, 53.4±4.1

Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005). "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs.". J Pharmacol Exp Ther 313 (2): 848-54.

The affinity of methcathinone and methamphetamine for DA/NA/5HT release is as follows:

EC50 DA/NE/5HT nM

(+)-Methamphetamine 12.3 ± 0.7, 24.5 ± 2.1, 736 ± 45
(–)-Methcathinone 13.1 ± 0.6, 14.8 ± 0.4, 1772 ± 160

Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA. (2003) In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates. J Pharmacol Exp Ther. 307(1), 138-145.

We can only make an educated guess that 4-Methylmethcathinone is somewhere between methcathinone and 4-Methylamphetamine in terms of 5HT release, and given that it's very possible we're dealing with a strongly neurotoxic and cardiotoxic agent. I mean, methamphetamine is incredibly neurotoxic yet is 60x preferential for DA over 5HT compared to 220x preferential for amphetamine, while 4-Methylamphetamine's ratio is 1.2x!

Think of the potential: An agent that could induce the apoptosis of dopaminergic and serotonergic neurons at many fold the pace of regular old methamphetamine!

 

[pofacedhoe]

This is a post from the other mephedrone thread, but it should probably be here too:



Think of the potential: An agent that could induce the apoptosis of dopaminergic and serotonergic neurons at many fold the pace of regular old methamphetamine!

interesting but people tend to notice feeling burned out on methamphetamine and as far as i was aware there were two mechanisms at action, one was like mdma in that dopamine gets drawn into the serotonin neurons reuptake mechanism due to serotonin depletion, the other was the burning out of dopamine neurons due to massive amounts of dopamine being released and peroxide metabolites being neurotoxic to dopamine neurons. mephedrone has clearly got weaker serotonergic effects than mdma but its dopamine effects are strong but dont seem to even match cocaine in my experience, i would hazzard a guess that it has a very strong adrenaline component but moderate dopamine effect. all i now is that after abusing mdma i felt awfull for months (long after alphamethyldopamine, and serotonin replenishment) but after mephedrone i felt fine two weeks later. i'm not defending this drug as i dont touch it anymore but i would doubt it is as neurotoxic as methamphetamine (although maybe more cardiotoxic) as its nowhere in the same league of dopamine effects as even amphetamine or cocaine (its more like an adrenaline rush). this is just subjective judgement based upon comparrison of the way the high feels.

 

[Rickyo]

This is a post from the other mephedrone thread, but it should probably be here too:

You don't even need to justify it by saying that it's a metabolite -- it's well know that putting a hydrophobic atom into the 4-position increases an amphetamine's affinity for SERT and thus serotonin release, which is well known to be a precursor for amphetaminergic neurotoxicity and cardiotoxicity.

EC50 DA/NE/5HT nM

d-Amphetamine 8.0±0.43, 7.2 ±0.44, 1756±94
meta-Methylamphetamine 33.3±1.3, 18.3±1.4, 218±22
para-Methylamphetamine 44.1±2.6, 22.2±1.3, 53.4±4.1

Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005). "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs.". J Pharmacol Exp Ther 313 (2): 848-54.

The affinity of methcathinone and methamphetamine for DA/NA/5HT release is as follows:

EC50 DA/NE/5HT nM

(+)-Methamphetamine 12.3 ± 0.7, 24.5 ± 2.1, 736 ± 45
(–)-Methcathinone 13.1 ± 0.6, 14.8 ± 0.4, 1772 ± 160

Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA. (2003) In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates. J Pharmacol Exp Ther. 307(1), 138-145.

We can only make an educated guess that 4-Methylmethcathinone is somewhere between methcathinone and 4-Methylamphetamine in terms of 5HT release, and given that it's very possible we're dealing with a strongly neurotoxic and cardiotoxic agent. I mean, methamphetamine is incredibly neurotoxic yet is 60x preferential for DA over 5HT compared to 220x preferential for amphetamine, while 4-Methylamphetamine's ratio is 1.2x!

Think of the potential: An agent that could induce the apoptosis of dopaminergic and serotonergic neurons at many fold the pace of regular old methamphetamine!

So Mephedrone is 40 times more neurotoxic than methamphetamine?!

 

[nuke]

So Mephedrone is 40 times more neurotoxic than methamphetamine?!

Well, mephedrone is probably 1/10th to 1/20th the potency too, and we just don't know how toxic 4-Methylamphetamine is yet, so it's hard to say. That it has a structure that's a combination of a known neurotoxin (METHCAT) and a putative neurotoxin (4-Me-AMP) is pretty damning.

interesting but people tend to notice feeling burned out on methamphetamine

I usually feel fine after methamphetamine so long as I don't avoid sleep. Same with MDMA. Aside from that people have reported nasty comedown from mephedrone. The comedown is also a function of the depletion of enzymes that synthesis serotonin and serotonin receptor hypersensitivity/up-regulation to compensate.

and as far as i was aware there were two mechanisms at action, one was like mdma in that dopamine gets drawn into the serotonin neurons reuptake mechanism due to serotonin depletion, the other was the burning out of dopamine neurons due to massive amounts of dopamine being released and peroxide metabolites being neurotoxic to dopamine neurons. mephedrone has clearly got weaker serotonergic effects than mdma but its dopamine effects are strong but dont seem to even match cocaine in my experience, i would hazzard a guess that it has a very strong adrenaline component but moderate dopamine effect.

There no proof that mephedrone releases less 5HT than either MDMA or METH at recreational doses. Going by 4-Methylamphetamine, everything points to it releasing more 5HT. The only thing reduced compared to MDMA is the ability to act as a 5HT2A/5HT2C substrate. The analysis of the SAR between related amphetamines and cathinones just looks terrible in terms of 5HT release.

all i now is that after abusing mdma i felt awfull for months (long after alphamethyldopamine, and serotonin replenishment) but after mephedrone i felt fine two weeks later. i'm not defending this drug as i dont touch it anymore but i would doubt it is as neurotoxic as methamphetamine (although maybe more cardiotoxic) as its nowhere in the same league of dopamine effects as even amphetamine or cocaine (its more like an adrenaline rush). this is just subjective judgement based upon comparrison of the way the high feels.

Your subjective feeling emotionally doesn't necessarily have to do with the encountered neurotoxicity. I've known a lot of people who would do MDMA every other week for the span of years and have little negative side effects (hell, look at Mrs. Shulgin), but the damage to your short-term memory and cognitive function is generally less easily perceived. And you can't just subjectively measure the effects of monoamine release.

The problem is that there's no empirical data to suggest it's not a neurotoxin, and we won't find out until someone feeds it to rats.

 

[MeDieViL]

Goddamn we really need some rat studies, hope it aint gonna take much longer.

 

[Rickyo]

Well, mephedrone is probably 1/10th to 1/20th the potency too,...

Sorry, don't quite get this bit - potency of what - Meth?