Direct Application of MDMA to the Brain is not Neurotoxic

[BilZ0r]

This article has some very interesting things to say on that subject.

Importantly for this discussion that it is very rare for MAO-B to be expressed in serotonergic terminals, and that it is normally expressed in the cell body... which would mean some very odd things...

* BilZ0r walks away confused.

 

[Ximot]

Though not particularly scientific, I feel compelled to contribute to the discussion simply for the anecdotal evidence I can give due to my 5 years of experience with daily SSRi (fluoxetine + sertraline) ingestion:

Basically I found that it does NOT stop MDMA from working. It just might take the edge off it, just as it allowed me to smoke WAY more cannabis without feeling uncomfortable and allowed me to take psychedelics without ever having even the hint of a freakout.

And I also have doubts whether SSRIs are really not neurotoxic. I, for one, had ever more unpleasant side effects of a physical and mental nature that took a while to get rid of even after I stopped taking those damn pills.

The other thing is - to what extent can a drug that doesn't "work" upon single ingestion but needs to be taken daily for some time before it does what it's meant to do work for the 5-HT reuptake inhibition related to MDMA use with just oen ingestion?

 

[BilZ0r]

Basically I found that it does NOT stop MDMA from working. You're not the only person I've heard report this. I often wonder if its because the people who say this are either on low doses, or are extensive metabolisers or some physiological reason.

And I also have doubts whether SSRIs are really not neurotoxic. I, for one, had ever more unpleasant side effects of a physical and mental nature that took a while to get rid of even after I stopped taking those damn pills.

A lot of people get bad side effects, and neurotoxicity, mixed up. A drug could make you feel like absolute, unbelievable shit (amphotericin, beta-interferon), but have absolutel no neurotoxic effects.

The other thing is - to what extent can a drug that doesn't "work" upon single ingestion but needs to be taken daily for some time before it does what it's meant to do work for the 5-HT reuptake inhibition related to MDMA use with just oen ingestion?

Well, the 5-HT reuptake inhibition happens straight away. So that points to the idea that the "anti-depressant" effects are subsequent to that.

 

[Ximot]

I must admit I haven't read thru all those research papers, but I got the impression that the neurotoxicity is about something else/more than just depleted serotonin levels (i.e exhausted glands due to to overstimulation beforehand).

Even if that were the only thing that makes MDMA neurotoxic, I think that the reuptake inhibition caused by an SSRi would merely be masking this neurotoxic effect caused by MDMA (the glandular exhaustion) by keeping the serotonin circulating in the bloodstream (thus masking the "Tuesday blues" or comedown or whatever).

I also have doubts whether this reuptake inhibition doesn't also mess with the pituitary gland (is that the one that produces melatonin/serotonin?) in some way. It just seems it will produce less serotonin simply because so much of it is circulating already. And when one stops taking an SSRI after having taken it for so long, a serious slump can occur - partly due to the gland not doing its job any more.

This is, again, totally not backed by any scientific research but just a gut feeling.

 

[BilZ0r]

We don't know what causes MDMA mediated neurotoxicity

SSRIs don't mask neurotoxicity. Results like this don't come from humans, they come from animals, where they can accurately measure neurotoxicity. And serotonin in regards to this topic, doesn't circulate in the bloodsteram.

The pituitary produces melatonin, and the serotonin precursor. But most serotonin is produces in neurons which have their cell bodies in the raphe nuclei.

It is likely that SSRIs increase auto-receptor negative feedback, and decrease 5-HT production. But ultimately, the produce in increase is 5-HT release (turnover).

But this really isn't the place for gut feelings... Maybe a Senior Mod could move these last coupley posts to a new thread in ED?

 

[VelocideX]

Basically I found that it does NOT stop MDMA from working. You're not the only person I've heard report this. I often wonder if its because the people who say this are either on low doses, or are extensive metabolisers or some physiological reason.

I seem to recall that binding of SSRIs at commonly administered doses is only of the order of 50% give or take a bit (i.e. not 99%). Surely this leaves room for concurrent binding by MDMA? How competitive are the SSRIs for the SERT? If the reaction is anything like an equilibrium then surely the MDMA can get involved during the SERT's "non-bound" period?

 

[BilZ0r]

Well amphetamines are very hard to think about in normal kinetic terms, because they are of couse, not receptor ligands, but transporter substrates (though I suppose the act as ligands to the extracellular binding cite at the same time)...

SSRIs definatly show equilibrium kinetics... and their antagonism of SERT sites isn't insurmountable at therapeutic doses... But ~50% binding should still seriously inhibit MDMAs action. (Which is reported by most)... as I say, I suspect people who don't report much effects of SSRIs on MDMA highs end up with low SERT occupancy for some reason.