Why did Nichols find MDAI to be non-neurotoxic in comparison to many other 5HT and...

[Cotcha Yankinov]

I think part of why the dopamine uptake into the serotonin terminal theory might apply especially to MDMA is because MDMA reduces tryptophan hydroxylase - maybe serotonin2A can chime in about the possible relevant time frames but I imagine that decreased tryptophan hydroxylase plays a role in neurotoxicity that occurs with binge administration over a couple days.

I guess my question would be does MDAI reduce tryptophan hydroxylase similar to MDMA? Unfortunately I think it might be hard to tell what is a true reduction of tryptophan hydroxylase and what is a loss of serotonin cell components.

 

[aced126]

The benzodioxole system would decrease DA transporter affinity and increase SERT affinity. This is why modifying methamphetamine with this substitution (to MDMA) significantly decreases DA release (compare meth to MDMA dosage) but also significantly increase 5HT release.

However if the compound is already 5-HT selective like NM-2-AI, then it's sister molecule MDMAI will have even lower DA affinity and more SERT affinity. But since DA affinity is already quite low, the reduction may not be enough to cause an observable reduction in neurotoxicity?

 

[Weltmeister]

I think part of why the dopamine uptake into the serotonin terminal theory might apply especially to MDMA

Can you post any study that proves the dopamine toxicity theory because i cant find them.

Theres a review from 2015 but it doesnt even mention it : https://www.researchgate.net/profil...mechanisms/links/563a4ad908ae337ef2984283.pdf

Edit:

a study checking for neurotoxicity in NM-2-AI would be cool. if it doesn't show any (looking at the same markers as ones looked for MDAI) then there's something on the MD ring which contributes too, not just the monoamine release (i know this isn't really related to your topic ace i'm kinda thinking out loud here).

According to wikipedia its not neurotoxic. https://en.wikipedia.org/wiki/NM-2-AI
The page cites this study : http://chemistry.mdma.ch/hiveboard/...tetralin.indan.non-neurotoxic.mda-analogs.pdf

 

[Cotcha Yankinov]

There are a couple studies that lend credence to the theory of dopamine uptake into the serotonin nerve terminal being one source of damage.

There are many studies that show that something is being taken up into the nerve terminal via the SERT, supporting that is that studies showing SERT inhibitors block neurotoxicity, as well as 5-HTP administration blocking neurotoxicity (anything that competes with the toxic compound for the SERT helps). Part of this might have to do with a MDMA metabolite.

The evidence that it is specifically dopamine is the study this thread is discussing - that amphetamine/DRA's cause non-neurotoxic MDMA analogues to become neurotoxic, as well as a study showing MAO-B inhibition greatly reduces neurotoxicity. Another study has confirmed that the SERT can transport dopamine into the serotonin nerve terminal (I believe it was in lymphocytes).

So there is evidence for it, I don't think Nichols would have proposed this theory otherwise, but I've thought about emailing him and asking him if he thinks it's still a plausible theory.

 

[serotonin2A]

I think part of why the dopamine uptake into the serotonin terminal theory might apply especially to MDMA is because MDMA reduces tryptophan hydroxylase - maybe serotonin2A can chime in about the possible relevant time frames but I imagine that decreased tryptophan hydroxylase plays a role in neurotoxicity that occurs with binge administration over a couple days.

I guess my question would be does MDAI reduce tryptophan hydroxylase similar to MDMA? Unfortunately I think it might be hard to tell what is a true reduction of tryptophan hydroxylase and what is a loss of serotonin cell components.

Effects on TH and loss of serotonergic terminals can be differentiated by comparing 5-HT levels and radioligand binding (eg, [3H]paroxetine) to SERT. MDMA depletes serotonin from vesicles but resynthesizing serotonin and refilling the vesicles should only take a few hours. If depletion lasts more than a few hours then it is more likely to be caused by inhibition of the enzymes responsible for synthesizing serotonin.

So if you look at the MDAI studies, check out the time-course of the 5-HT depletion, as well as the paroxetine binding data. That will give you the answer regarding whether TH is probably inhibited. If serotonin levels are down for a few days after MDAI but paroxetine binding is mostly intact then the results probably reflect TH inhibition.