2C-*s and MDMA-like serotonin flood?

[solistus]

I've read before that 2Cs are speculated by some to produce a serotonin reuptake inhibiting effect analogous to MDMA. I have two questions about this:

1. Anyone know of any actual hard evidence backing this up beyond people saying "it feels similar?" Scientific studies finding actual evidence of increased serotonin levels, that sorta thing? Seems like it would be easy enough to corroborate or deny once and for good, but I'm no neurochemist.

2. If there is any evidence to back it up, would this potentially mean 2Cs have some of the same health and safety risks as MDMA, particularly regarding repeated use over a short time? I ask this for two reasons, both stemming from my own 2C-E and -I experiences: one, I've used 2Cs repeatedly within short timeframes many times and would like to find out if doing so is likely for any particular reason to cause any sort of neurological damage, and two, based on that repeated 2C use, I have noticed no obvious tolerance effect of any kind, let alone one as dramatic as with MDMA (I have on a handful of occasions been stupid and irresponsible and taken MDMA without waiting a couple weeks between rolls and had very weak experiences with exaggerated side effects and very little euphoria), although I also don't find them to be nearly _as_ consistently euphoric as molly either - nothing, except perhaps strong opiates, compares to the sheer enjoyability of an MDMA roll to me.

So, without rambling on any further... Anyone got any solid info to share on all of this, or is it all just speculation based on subjective similarity?

 

[Amberthefrog]

MDMA is a serotonin reuptake inhibitor?

 

[Solipsis]

AFAIK it is, but not typically. Isn't serotonin reuptake negated by MDMA messing around with your transporters? So not only is serotonin not being taken up again, it is released by that route as well, while dopamine can be taken into the synapse.

This is what I believe I learned about MDMA neuropharmacology.

I thought 2C-X don't inhibit serotonin reuptake but cause all their effects by agonizing serotonin receptors.

 

[danceofdays]

I've never gotten the crazy MDMA pleasure rushes from 2C-B or 2C-I, although both were very euphoric in an amphetamine-type way. So maybe they do have some uptake inhibition action. I always thought MDMA flooded the synapse with a huge fresh dose of serotonin, hence the "rush".

 

[psood0nym]

2C's likely do release monoamines in the human body, but not nearly as strongly as MDMA, meth, or aMT. They certainly feel like they have more no-strings-attached chemical pleasure than tryptamines to me. See this study. From the abstract:

2,5-dimethoxy-4-
iodophenethylamine (2C-I), 2,5-dimethoxy-4-ethylphenethylamine (2C-E), 2,5-dimethoxy-4-
chlorophenethylamine (2C-C), 2,4,5-trimethoxyamphetamine (TMA-2) and 2,4,6-
trimethoxyamphetamine (TMA-6), which are methoxylated phenethylamine derivatives,
slightly influenced the re-uptake and release of monoamines.

 

[solistus]

I was under the impression that there were still two competing and unconfirmed theories regarding MDMA's mechanism of action: one that it operates primarily more or less as a very unique variety of SSRI, the other that it stimulates additional serotonin release... Anyway, I'm no expert on the neurochemistry of MDMA and I haven't read up on the scientific data in quite some time.

At any rate, am I correct then in believing that there is no specific evidence of any sort of serotonin flood effect that would lead to neurological damage with repeated use as does MDMA?

In general, my basic understanding of classic psychedelics versus MDMA is that psychedelics typically agonise 5HT2a, changing the way the brain interprets serotonin somehow, whereas MDMA results in a higher concentration of serotonin. Is that about right?

 

[TheAzo]

MDMA has repeatedly been shown to be a serotonin release agent. It increases concentrations of serotonin, dopamine, and norepinephrine.

Psychedelics have their effects by activating the 5HT2A receptor (a specific subtype of serotonin receptor, of which there are many), and not any of the other serotonin receptors. Probably activate it more strongly (and in qualitatively different ways) than serotonin itself.

 

[psood0nym]

At any rate, am I correct then in believing that there is no specific evidence of any sort of serotonin flood effect that would lead to neurological damage with repeated use as does MDMA?

In general, my basic understanding of classic psychedelics versus MDMA is that psychedelics typically agonise 5HT2a, changing the way the brain interprets serotonin somehow, whereas MDMA results in a higher concentration of serotonin. Is that about right?

I remember reading a posting on Erowid from MAPS years ago that recommended taking measures to minimize damage when using phenethylamines (antioxidants and such) because they have been found to be more neurotoxic than the well-known tryptamines. I've heard anytime there's substantial release of dopamine and serotonin, as with the phenethylamines listed in the study I posted, some damage is inevitable. Still, I doubt it's that much. Halpern's cognitive and emotional tests of long-term ceremonial peyote users found no detriments versus clean controls and better than control emotional well-being.

 

[Roger&Me]

Psychedelics have their effects by activating the 5HT2A receptor (a specific subtype of serotonin receptor, of which there are many), and not any of the other serotonin receptors.

Ehh...not exactly.

It turns out there are actually very few selective 5HT2A agonists; most psychedelics exert their effects through interaction with many different types of receptor sites. Check out the "psychedelics and the human receptorome" thread in ADD for more info.

 

[solistus]

^^^ Although, IIRC, the 2Cs in general were some of the closest to a truly selective 5HT2a agonist as per that study, IIRC. One of them in particular was singled out as a near perfect selective agonist at 5HT2a - I think it was either 2C-E or one of the 2C-Ts?

psood0 - if you happen across a source, let me know. I wasn't aware of any research from quality sources generalising the effects of PEAs. I'm pretty familiar with the mescaline/peyote literature and, as you said, it's generally not known to cause long term problems for its users. Given the harms associated with the alpha-methylated members of this family (aka amphetamines), though, it wouldn't surprise me if PEAs in general are seen as a risk area.

I read up on wiki about MDMA, and I remember what I was thinking of. The original theory was that it just inhibits serotonin reuptake; the current popular theory is that A) it not only inhibits reuptake but reverses it, re-releasing the serotonin instead of recycling it - a little off from my recollection of stimulating production but the same basic effect of more serotonin release overall; and B) it does the same thing for norepinephrine and dopamine, as you said, although it seems that its effects on 5HT are better understood, or at least explained in more detail on wikipedia..

 

[Roger&Me]

One of them in particular was singled out as a near perfect selective agonist at 5HT2a - I think it was either 2C-E or one of the 2C-Ts?

Yeah I think that was 2C-E, which was quite intriguing to me-- it being quite the enigmatic beast of a psychedelic.

 

[JBrandon]

The damage that MDMA induces is thought to be pretty varied...

You'll see talk about receptor downregulation and harsh oxidative damage. A lot of people float the theory that dopamine gets pulled into the serotonin nerve axon terminals and the metabolites from the degradation of dopamine do the damage. I believe it's possible that the combination of both oxidative stress and downregulation is the likely culprit behind some of the MDMA horror stories you hear.

My completely speculative guess would be that with most of the 2Cs, receptor downregulation from chronic use would be much more likely of a threat than the SAME type of oxidative damage that MDMA causes.

Who knows though, maybe they have their own unique and unknown mechanism of damage that will put us all in a nursing home in 10 years!

 

[solistus]

Receptor downregulation is in most cases temporary, isn't it? I was under the impression that was thought to be the mechanism for many forms of drug tolerance, unless that's something else. LSD, mushrooms, etc. seem to have a similar short term tolerance effect which I assumed was due to temporary downregulation of 5HT2a. That or I'll have another of my pharmacological misconceptions corrected on this thread

Given that 2C-B and mescaline are both relatively well studied and not known to be neurotoxic or otherwise likely to cause serious or long term complications aside from contraindicated combinations (e.g., mixing with MAOIs), I feel relatively safe in light to moderate frequency of use and not extremely worried about at least short term binges. HPPD seems to be the only somewhat documented potential complication, which seems to be possible with any visually active psychedelic as far as I'm aware although it may be more common and/or well documented with some.

 

[swilow]

Yeah I think that was 2C-E, which was quite intriguing to me-- it being quite the enigmatic beast of a psychedelic.

Isn't DOB the strongest serotonin agonist. ie. full agonist?

I'd say the downregualtion of 5HT2a recetpors probably accounts for the afterglow of psychedelics; ie. same amount of cerebral serotonin, less receptors to bind to. That could just be uttely stupid conjecture though...

 

[Saucy]

^I'm pretty sure that most of the phenethylamine / amphetamine derivatives with (di/tetra)hydrofuran rings are more potent agonists than any of the DOx's. I may be mistaken, but I seem to remember reading that bromo-Dragonfly displaces virtually every other serotonin agonist when administered in combination. Can someone confirm this?

 

[Amberthefrog]

Interesting! It's been a long time since I read up on proposed methods of action for MDMA. It does makes sense for it to affect the serotonin transporters though.

^I'm pretty sure that most of the phenethylamine / amphetamine derivatives with (di/tetra)hydrofuran rings are more potent agonists than any of the DOx's. I may be mistaken, but I seem to remember reading that bromo-Dragonfly displaces virtually every other serotonin agonist when administered in combination. Can someone confirm this?

The vast majority of 5-ht agonists are only partial in their action - this covers the vast majority of psychedelics and the vast majority of amphetamines. There are only a handful of full (on 5-ht2a I assume) agonists, bromo dragonfly is indeed one of these as are at least two of the DOx's, though which two they are escapes my memory - pretty sure DOB is one of them and I think the other is DOI or DOC. I'm fairly sure that DOM is only a partial agonist. As far as my knowledge goes, what you say regarding b-dragonfly makes sense as it is both a full agonist and incredibly potent (more so than the DOx full agonists even).

I'd say the downregualtion of 5HT2a recetpors probably accounts for the afterglow of psychedelics; ie. same amount of cerebral serotonin, less receptors to bind to. That could just be uttely stupid conjecture though...

Never thought about or heard that idea before, sounds appealing to me!

I was under the impression that there were still two competing and unconfirmed theories regarding MDMA's mechanism of action: one that it operates primarily more or less as a very unique variety of SSRI, the other that it stimulates additional serotonin release... Anyway, I'm no expert on the neurochemistry of MDMA and I haven't read up on the scientific data in quite some time.

At any rate, am I correct then in believing that there is no specific evidence of any sort of serotonin flood effect that would lead to neurological damage with repeated use as does MDMA?

I think you are correct in saying that.

 

[stirfry]

sorry to go off topic, but...

2C's likely do release monoamines in the human body, but not nearly as strongly as MDMA, meth, or aMT. They certainly feel like they have more no-strings-attached chemical pleasure than tryptamines to me. See this study. From the abstract:

Awesome find! That was a very interesting study, thanks for posting it. I found it surprising how similar aMT and MDMA are in their monoamine releasing properties, yet MDMA and Methylone have such clear differences.

 

[Roger&Me]

Isn't DOB the strongest serotonin agonist. ie. full agonist?

I'd say the downregualtion of 5HT2a recetpors probably accounts for the afterglow of psychedelics; ie. same amount of cerebral serotonin, less receptors to bind to. That could just be uttely stupid conjecture though...

Well, I don't remember the details pertaining to DOB but (according to the "human receptorome" thread in ADD) supposedly DOI was thought to be a full agonist of 5HT2A but actually isn't. I would expect that to apply to DOB as well.

Keep in mind that this is only based on the results of one study-- but if the results of that study are replicated and prove valid, it changes the whole way we think about the pharmacology of psychedelics.

 

[psood0nym]

Stirfry: Dondante posted it originally in the B&D aMT thread a while back. It is one of the best sources of info on this topic, no doubt, but it's still possible things work a lot differently inside the human brain than they do for rat synaptosomes.

 

[Coolio]

This thread probably belongs in Advanced Drug Discussion if you want more complete answers.