• N&PD Moderators: Skorpio | thegreenhand

Making Sense of the Fact that MDMA has a poor affinity for SERT

there's this paper about mdma and 5-ht2b: http://www.ncbi.nlm.nih.gov/pubmed/18337424

basically it says that there's no serotonin release in mice without 5-ht2b receptors. also both mdma and mda as well as the rc's that qualify most as "mdma replacements" have significant activity there. so this may be the main component in mdma-mediated 5-ht release...
 
there's this paper about mdma and 5-ht2b: http://www.ncbi.nlm.nih.gov/pubmed/18337424

basically it says that there's no serotonin release in mice without 5-ht2b receptors. also both mdma and mda as well as the rc's that qualify most as "mdma replacements" have significant activity there. so this may be the main component in mdma-mediated 5-ht release...

Excellent, their followup paper on the role of 5HT2B in antidepressant action looks good too:

http://www.ncbi.nlm.nih.gov/pubmed/22158014
 
there's this paper about mdma and 5-ht2b: http://www.ncbi.nlm.nih.gov/pubmed/18337424

basically it says that there's no serotonin release in mice without 5-ht2b receptors. also both mdma and mda as well as the rc's that qualify most as "mdma replacements" have significant activity there. so this may be the main component in mdma-mediated 5-ht release...

You very well may be right there. Does anyone know of a strong 5-ht2b agonist that doesn't cause 5-HT release? Fenfluramine, MDMA, every 5-HT2b agonist I can think of causes release.

It would be very unfortunate if 5-HT2b agonism was required for empathogenic effects. That would mean the desired effects and the long term cardiotoxicity are unseparable.
 
Excellent, their followup paper on the role of 5HT2B in antidepressant action looks good too:

http://www.ncbi.nlm.nih.gov/pubmed/22158014

nice find, i didn't see that one. going to read it now :)

You very well may be right there. Does anyone know of a strong 5-ht2b agonist that doesn't cause 5-HT release? Fenfluramine, MDMA, every 5-HT2b agonist I can think of causes release.

It would be very unfortunate if 5-HT2b agonism was required for empathogenic effects. That would mean the desired effects and the long term cardiotoxicity are unseparable.

yes, even amt as a tryptamine is no exception.

sadly it looks like it :(. one could take a centrally active agonist in combination with an anatagonist that can't cross the blood-brain-barrier similar to what they do with levodopa/carbidopa, but of course that's impractical.
 
Does 4-fluoroamphetamine have action @ the 5ht2b receptor? It definitely has mdma-like empathogenic effects for me..
but then again if something releases serotonin.. the serotonin will activate the 5ht2b receptor anyway, maybe not as strongly or specifically..


I'm curious though, it still doesn't explain how mdma and mda aren't cross tolerant... in the study they dosed MDMA to build tolerance and then checked if MDA still worked, but I wonder if MDA was used first to build tolerance would MDMA still work after? To me it seems like that would be important information to have before concluding "that MDMA and MDA are not cross-tolerant," since it would give insight to their differences.

For example, if MDA dosed to max tolerance stopped MDMA from working you could conclude that MDA has additional effects apart from MDMA that allow it to continue to work, rather than them working through completely different mechanisms.
 
You very well may be right there. Does anyone know of a strong 5-ht2b agonist that doesn't cause 5-HT release? Fenfluramine, MDMA, every 5-HT2b agonist I can think of causes release.

It would be very unfortunate if 5-HT2b agonism was required for empathogenic effects. That would mean the desired effects and the long term cardiotoxicity are unseparable.

Well - see all the recent debate about NBOMe's having high affinity for 5HT2B, and that extends to other psychedelics, e.g. psilocin. I'm not aware of any efficacy data on psychedelics at 5HT2B though, maybe they are weak partial agonists?
 
Well - see all the recent debate about NBOMe's having high affinity for 5HT2B, and that extends to other psychedelics, e.g. psilocin. I'm not aware of any efficacy data on psychedelics at 5HT2B though, maybe they are weak partial agonists?

ah i misread that one. it sure looks like 5-HT2B agonism is necessary but not sufficient for serotonin release.

lsd has its highest affinity for 5-HT2B and according to this paper (which sadly only looks at Ca2+ release in CHO cells) a partial agonist (with nearly 50% realtive efficacy). on the other hand mdma also only has about 50% efficacy.
 
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