Raising Awareness for 5-Chloro-aMT and 5-Fluoro-aET

[Lobular]

So I've been lurking Bluelight for quite some time before finally making an account and in all my time I have never once even seen a discussion about either of these two compounds in any length - which to me is quite surprising even a cursory Wikipedia article reading of 5-Chloro-aMT in particular gives you a very promising impression that this compound is quite special and it seems like this forum is always brimming with excitement for new RC psychedelics. First and foremost, these two compounds are, so far, the only two known selective serotonin-dopamine releasing agents in the entire history of pharmacology - 5-Chloro-aMT in particular is a highly selective and well balanced SDRA with EC50 values for serotonin, dopamine, and norepinephrine release being 16 nM, 54 nM, and 3434 nM respectively (correspondingly giving it roughly 64-fold selectivity for dopamine over norepinephrine and 3-fold selectivity for serotonin over dopamine). You might be wondering what value a selective SDRA would even have over a SNDRA psychedlic like the parent compounds aMT and aET. Well this is largely speculation on my part but I do believe it is logically founded; norepinephrine release (as well as adrenergic receptor agonism) is what is usually implicated in host of nasty side effects while not really over much, if any, recreational value. This includes psychological effects such as anxiety, agitation, and even aggressiveness as well as several sypathomimetic and cardiovascular complications such as tachycardia, insomnia, restlessness, and shortness of breath. Especially for drugs as sensitisizing as psychedelics anxiety can properly ruin an experience. One of the most common complaints I read about aMT and aET (which do have a norepinephrine releasing component) is that it has a "dirty" feeling for some as a result of over-stimulation. In contrast, I could compare it to another halogenated drug of the stimulant class - 4-FA - which is said to feel quite "clean" in large part due to its limited A1 receptor agonism and norepinephrine reuptake inhibition. On top of that, both 5-Chloro-aMT and 5-Fluoro-aET are both full agonists to 5HT-2A receptor subfamily (5-Chloro-aMT has an EC50 value of 6.27 nM and an efficacy of 105%) which means they are very likely to be potent, full-bodied (if you will) psychedelics. To this effect, 5-Fluoro-aET has shown to produce a strong head-twitch response in rats during lab studies which is highly correlated with psychedelic response in humans; it is highly probable 5-Chloro-aMT also possess this quality. This addresses the other most common complaint people have with aMT and aET: that they are somewhat lacklustre psychedelics in their own right - lacking profound changes in thought or perception. The lack of profundity of those two compounds likely is the result of their somewhat less potent binding affinity and only partially agonistic efficacy at the 5HT-2A receptor. Unfortunately, 5-Chloro-aMT and 5-Fluoro-aET with still likely have one of the other problems that their parents compounds have and that's very possible effect as a RIMA (or MAO-A inhibitor) which while they relatively weak in this regard could potentially cause dangerous interactions if taken with other potent serotonin releasing agents such as MDMA. On top of that, just like practically all potent serotonin and dopamine releasing agents the potential for neurotoxicity is very real although there is reason to believe it still won't be as severe as MDMA (which itself is not an enormous concern). As with the parent compounds it will be prudent to cautiously dose and avoid hazardous drug combinations. In summary, I for one am very excited to see these two compounds enter the grey and black markets and hope I may test them myself even if only to experience their uniqueness; however, it is worth noting that with all of the engineered RC tryptamines they will probably be a bit costly to produce but that didn't stop the other from becoming fairly popular. To finish I'll leave you with a quote from a study done on these two compounds: "The unique combination of dual DA/5-HT releasing activity and 5-HT_2A receptor activity suggests that these compounds could represent a new class of neurotransmitter releasers with therapeutic potential."
Citations:
https://en.wikipedia.org/wiki/Serotonin-dopamine_releasing_agent
https://en.wikipedia.org/wiki/5-Chloro-αMT
http://www.sciencedirect.com/science/article/pii/S0960894X14007860
http://psycnet.apa.org/journals/pha/22/3/274/

 

[Jonneh]

They do sound like interesting compounds. I'm not sure there's a lack of interest here - it just that not many people have tried them because they aren't widely available.

I don't think you're right that norepinephrine release or reuptake inhibition = dirtiness. (Meth)amphetamine itself is a case in point, and 4-FA is a pretty potent norepinephrine reuptake inhibitor and releaser - similar to d-(meth)amphetamine.

EDIT: The wiki for 5-chloro-AMT is oddly detailed for such an obscure compound, and makes many of your points. Did you write it, perchance?

 

[Don Luigi]

I just want to know how much he's selling it for

 

[Jonneh]

^ If it weren't for those pesky Bluelight rules, we'd know, but it, and share the love of a perfect drug (finally).

Also, if methoxy substitution at the 5 position is anything to go by, increased psychedelia might come with all-around nastiness (whatever might be happening to norepinephrine). I'm not sure this augurs well for the halogen subs.

 

[Lobular]

They do sound like interesting compounds. I'm not sure there's a lack of interest here - it just that not many people have tried them because they aren't widely available.

I don't think you're right that norepinephrine release or reuptake inhibition = dirtiness. (Meth)amphetamine itself is a case in point, and 4-FA is a pretty potent norepinephrine reuptake inhibitor and releaser - similar to d-(meth)amphetamine.

EDIT: The wiki for 5-chloro-AMT is oddly detailed for such an obscure compound, and makes many of your points. Did you write it, perchance?

I could be wrong as to the exact effects of selectivity over norepinephrine release, but I can give a quote taken from the psychonaut wiki page for 4-FA: "Studies demonstrate that 4-flourine amphetamine substitutions limit activity of the compound at the alpha-1 adrenergic receptor with an over 200-fold increased selectivity for A2 receptors over A1 receptors.^[6] It has also been demonstrated that 4-substitution of a hydrogen with fluorine on the aromatic ring of norepinephrine produces a beta-adrenergic agonist with little alpha activity.^[7]This has led the online community to speculate that the milder uncomfortable cognitive and/or physical side effects and greater efficacy as a nootropic associated with this substance are at least partially due to decreased activity at the alpha-1 adrenergicreceptors resulting in significantly less norepinephrine reuptake inhibition."

As for the wikipedia page for 5-Chloro-aMT, I did not write any of it - although I have no way of proving that. I found it after searching for "serotonin-dopamine releasing agent" and it was the only listed ligand to fit that description.

 

[Jonneh]

I could be wrong as to the exact effects of selectivity over norepinephrine release, but I can give a quote taken from the psychonaut wiki page for 4-FA: "Studies demonstrate that 4-flourine amphetamine substitutions limit activity of the compound at the alpha-1 adrenergic receptor with an over 200-fold increased selectivity for A2 receptors over A1 receptors.^[6] It has also been demonstrated that 4-substitution of a hydrogen with fluorine on the aromatic ring of norepinephrine produces a beta-adrenergic agonist with little alpha activity.^[7]This has led the online community to speculate that the milder uncomfortable cognitive and/or physical side effects and greater efficacy as a nootropic associated with this substance are at least partially due to decreased activity at the alpha-1adrenergicreceptors resulting in significantly less norepinephrinereuptake inhibition."

Well, as ever, it's all about balance. There aren't many (if any) drugs that specifically act on dopamine (either as a releaser or via reuptake inhibition), but I suspect their effects would be more similar to modafinil than amphetamine - dopamine is all about attention and expectation after all. Where fairly specific drugs do exist (e.g. amineptine), they very much verge on the functional side of things, rather than the recreational.

Basically, I think the side effects of norepinephrine activity are part and parcel of the recreational value (although as with anything, one can overdo it).

 

[Lobular]

Well, as ever, it's all about balance. There aren't many (if any) drugs that specifically act on dopamine (either as a releaser or via reuptake inhibition), but I suspect their effects would be more similar to modafinil than amphetamine - dopamine is all about attention and expectation after all. Where fairly specific drugs do exist (e.g. amineptine), they very much verge on the functional side of things, rather than the recreational.

Basically, I think the side effects of norepinephrine activity are part and parcel of the recreational value (although as with anything, one can overdo it).

I don't think modafinil is a very good counter-example being that is both an incredibly weak and atypical dopamine reuptake inhibitor. I imagine if you took something like methylone and somehow were able to block out the norepinephrine release you'd find it was still a nicely euphoric experience without some of the edginess. Of course I'm not sure that would really be possible and until now we've operated under the assumption that dopamine and norepinephrine release were inextricably linked.

 

[Dresden]

I'm more eager to try 4-chloro-AMT due to its more structural similarity to psilocin and less structural similarity to the truly nasty 5-MeO-AMT which put people into the hospital for months sometimes having to learn to walk again. But I'd like to try 5-choro-AMT too based on what you shared.

4-CHLORO-AMT

 

[Jonneh]

I don't think modafinil is a very good counter-example being that is both an incredibly weak and atypical dopamine reuptake inhibitor. I imagine if you took something like methylone and somehow were able to block out the norepinephrine release you'd find it was still a nicely euphoric experience without some of the edginess. Of course I'm not sure that would really be possible and until now we've operated under the assumption that dopamine and norepinephrine release were inextricably linked.

My counter example was really amineptine (which happens to have focus and attention-centred effects comparable to modafinil) - clean, for sure, but not recreational. From what we know of the computational role of dopaminergic circuits in the brain, I just don't expect their specific activators to have euphoric effects. Strong enough empirical evidence can out-compete even strongly weighted theory, though, so we'll just have to wait and see.

 

[Lobular]

My counter example was really amineptine (which happens to have focus and attention-centred effects comparable to modafinil) - clean, for sure, but not recreational. From what we know of the computational role of dopaminergic circuits in the brain, I just don't expect their specific activators to have euphoric effects. Strong enough empirical evidence can out-compete even strongly weighted theory, though, so we'll just have to wait and see.

You'll have to forgive my ignorance on this subject; my knowledge neurological psychology leaves much to be desired. It was my understanding that dopamine is a "conditioner" of sorts that influence brain reward pathways. By this effect, I guess it would make sense that dopamine alone wouldn't create euphoria but merely facilitates another interaction's rewarding capacity. I looked up a study that found that even two largely diametrically opposed psychoactive drugs (in terms of their mechanisms) create euphoria through dopamine pathways - specifically it found that both opiates and amphetamines both use dopamine to create reward and thereby euphoria (the link to the study is below). Even a drug like GHB which doesn't seem to have any interaction with norepinephrine at all creates euphoria through increases of both glutamate and dopamine. So to relate back to the thread topic (finally), 5-Chloro-aMT doesn't solely release dopamine - it also releases over three times as much serotonin. The question remains: would serotonin AND dopamine release by themselves be sufficient to produce euphoria? I have even heard some accounts of people feeling mild euphoria from MDAI; which is a pure serotonin releaser. Personally, I believe that selecting out norepinephrine would merely create less side effects such as anxiety and insomnia, but I could be wrong and maybe it'll lose out on a lot of recreational value.

The link to the study referenced above: http://www.ncbi.nlm.nih.gov/pubmed/2893431

 

[ketaman123]

The closest I have gotten to these substances is AET and 5-MeO-AMT. I am particularly interested in 5-Chloro-AMT, for Dresden's reasoning

 

[Jonneh]

You'll have to forgive my ignorance on this subject; my knowledge neurological psychology leaves much to be desired. It was my understanding that dopamine is a "conditioner" of sorts that influence brain reward pathways. By this effect, I guess it would make sense that dopamine alone wouldn't create euphoria but merely facilitates another interaction's rewarding capacity. I looked up a study that found that even two largely diametrically opposed psychoactive drugs (in terms of their mechanisms) create euphoria through dopamine pathways - specifically it found that both opiates and amphetamines both use dopamine to create reward and thereby euphoria (the link to the study is below). Even a drug like GHB which doesn't seem to have any interaction with norepinephrine at all creates euphoria through increases of both glutamate and dopamine. So to relate back to the thread topic (finally), 5-Chloro-aMT doesn't solely release dopamine - it also releases over three times as much serotonin. The question remains: would serotonin AND dopamine release by themselves be sufficient to produce euphoria? I have even heard some accounts of people feeling mild euphoria from MDAI; which is a pure serotonin releaser. Personally, I believe that selecting out norepinephrine would merely create less side effects such as anxiety and insomnia, but I could be wrong and maybe it'll lose out on a lot of recreational value.

The link to the study referenced above: http://www.ncbi.nlm.nih.gov/pubmed/2893431

Not to worry - it sounds like you have a good grasp of it, and in the details, it is almost a philosophical issue we're discussing.

Take a look at this paper: http://www.jneurosci.org/content/23/28/9395.long. (Specifically-) hyperdopaminergic mutant mice want more sweet rewards, but they don't actually enjoy them any more than normal mice (less, actually). There is a caveat here, which is that the mutation caused decreased reuptake and not increased release, and therefore an increase in tonic but not necessarily phasic dopaminergic signalling, which may be important (see http://europepmc.org/articles/pmc4064368). But the general message is that other neurotransmitter systems provide the context needed for a liking (euphoric) reaction.

All this to say that serotonin activity (alongside dopamine) induced by e.g. 5-chloro-AMT may well be sufficient to produce euphoria, and possibly of a less anxious nature than if it acted on dopamine and norepinephric axes, but one probably need something else, alongside dopamine.

 

[Morninggloryseed]

fascinating stuff

 

[Solipsis]

Purely dopaminergic stimulants can be quite functional and have very limited euphoria / recreational value...

Instead from what I recently picked up in NSP it seems rather that it is certain receptors in the reward circuits that are coupled to other receptors and facilitate feedback of other kinds of neurotransmitters that lead to euphoria (and I'd care to venture also addiction). GHB is probably a bad example since not only are GABA receptors heavily implicated as those coupled receptors / feedback, I think that GHB receptors probably also matter a lot here. But all in all, you're right that various kinds of drugs can produce euphoria and addiction that purely looking at the direct pharmacodynamics don't seem to be implicated - that is, until you consider those coupled receptors.

And yes dopamine and reward is really weird - dopamine does facilitate the reward, but normally expectations raise the stakes so to speak. I remember semi counterintuitive phenomena from animal experiments and dopamine / reward but not sure what they were..

@ 5-Chloro-AMT :

Seems doubtful that it's worth heavy MAO inhibition. In normal aMT the MAO inhibition is rather limited, and if you only take aMT the overdose territory seems quite high. Above 100 it gets tricky, above 150 mg dangerous... but 1000 mg is known to be fatal but in between uncertain. So yeah unless you combine aMT is not quickly a contraindication for itself but 5-MeO-aMT seems already much more of a poor idea. Even if the effects of 5-Chloro-aMT are pleasant it is probably better if we don't have another 5-MeO-aMT therapeutic index wise.

If 4-Chloro-DMT is interesting, that may be a much better idea and it should also be a lot easier to work with in the lab than psilocin's labile indolol function. 4-Chloro-aMT meh, I don't recall 4-HO-aMT being good. 5-halo-DMT like the bromo is reported to be good... and it's still a little vague what makes bufotenin sketchy but if 5-halo-DMT is effective as bufotenin but without people getting purple and tight-chested that seems like a good plan.

 

[Lobular]

Seems doubtful that it's worth heavy MAO inhibition. In normal aMT the MAO inhibition is rather limited, and if you only take aMT the overdose territory seems quite high. Above 100 it gets tricky, above 150 mg dangerous... but 1000 mg is known to be fatal but in between uncertain. So yeah unless you combine aMT is not quickly a contraindication for itself but 5-MeO-aMT seems already much more of a poor idea. Even if the effects of 5-Chloro-aMT are pleasant it is probably better if we don't have another 5-MeO-aMT therapeutic index wise.

If 4-Chloro-DMT is interesting, that may be a much better idea and it should also be a lot easier to work with in the lab than psilocin's labile indolol function. 4-Chloro-aMT meh, I don't recall 4-HO-aMT being good. 5-halo-DMT like the bromo is reported to be good... and it's still a little vague what makes bufotenin sketchy but if 5-halo-DMT is effective as bufotenin but without people getting purple and tight-chested that seems like a good plan.

Actually according to the Wikipedia page on 5-Meo-aMT it is speculated (although there is no source so I would take this with a grain of salt) that "It is likely that the overdose potential of the compound is due to its sympathomimetic effects, as the side effects noted in overdose cases include cardiac arrhythmia and seizure. It also seems that oral consumption is safer than insufflation". Whereas 5-Chloro-aMT would have effectively zero sympathomimetic side effects due to its explicit lack of noradrenaline release or reuptake inhibition. That being said I in no way doubt that serotonin toxicity due to MAO-A inhibition could pose a real threat; we'll have to await further research I suppose.

https://en.m.wikipedia.org/wiki/5-MeO-aMT

 

[Solipsis]

Possible consequences of NBOMe overdose can also be seizures, multi organ failure and I bet arrhythmia's are not out of the question. "Sympathomimetic effects" is a very broad term that can basically involve any of the stimulatory neurotransmitters. The pharmacology of 5-MeO-aMT has not been established and neither the similarity of aMT or DOX to amphetamines should be confused as evidence for toxicity. aMT has stimulant effects but acts distinctly different from amphetamine, DOX do too.

NBOMe's like 25I are mostly considered to be 5HT2A agonists yet on occasion they can kill people. We aren't even fully aware what happens with 2C-T's although it seems that they share some pharmacology with MDMA and/or MAOIs.

So no you can't really say that 5-Chloro-aMT is probably safe or anything of the sort. Serotonergic effects can still clearly be a source of sympathomimetic toxicity as serotonin relays messages within the sympathic nervous system, while pure serotonergics like MDAI are usually not stimulating, serotonergic effects can still be serious.

The source of NBOMe toxicity remains a mystery and with it, serotonergic involvement can not be excluded as a potential source of severy toxicity. We should not pretend to understand NBOMe's nor 5-MeO-aMT (or 2C-T's) as far as toxicity involving psychedelics ins concerned.