MDMA, anti-depressants, tramadol, etc.

[ebola?]

Hi. So we all know that SSRIs will reduce the effect of MDMA because most all SSRIs have greater binding affinity for the SERT than MDMA, kicking MDMA off these sites, but causing no direct release of 5ht. DXM, on the other hand, is contradicted with MDMA because it increases inter-cellular serotonin without occluding the SERT, and the combined effect runs the risk of inducing serotonin syndrome.

What about tramadol? It increases 5ht but supposedly doesn't block SERT.

And what about atypical anti-depressants? EG, Remeron (mirtazapine) increases 5ht indirectly. Yet it is not contraindicated with MDMA. What gives?

ebola

 

[ebola?]

Hate to bump this, but this might be ADD material.

 

[indelibleface]

Yeah, thanks for reminding me -- moving now...

I actually brought this up with ebola? during the weekend, so it's partly my question as well.

Very curious!

 

[theWorldWithin]

This is just speculation but maybe the sitution is that the atypical AD's increase 5-ht in a more indirect and downstream fashion than more traditional AD's. The downstream action could have a hard celling on 5-ht concentration increases because of its indirect activity, and thus not provide enough of an excess to put users in any danger when combined with MDMA. Where does Remeron bind?

Also keep in mind that DXM is contraindicated partly because of its effect on thermal regulation. My understanding is that extremely elevated body temperature puts users at greater risk for developing serotonin syndrome. When you consider that both DMX and MDMA increase body temp significantly and serotnin syndrome also features increased temperature you have a very dangerous run away situation where the temp increases can cause more temp increases by inducing more severe SS and so on.

But really this is just my 2 cents, keep the change

 

[indelibleface]

I guess my root question with all of this was in regards to tramadol.

If it's an SSRI, what makes it so dangerous to take with MDMA?
Don't SSRIs block the mechanism of MDMA in the brain? Why would serotonin syndrome be an issue?

 

[nuke]

Yes, they do. I've known many many many people who have taken MDMA on SSRIs and none of them experienced anything like serotonin syndrome (not surprising given the studies of rats being pretreated with an SSRI then given large doses of MDMA). It has an effect on NE reuptake also, so that could further diminish the response to MDMA.

Tramadol also lowers the seizure threshold, so that could be a big worry if you're combining it with large amounts of a stimulant that also do.

DXM increases body temperature?

Several amphetamine analogs, when administered in high-dose regimens, have been shown to cause long-lasting depletions of central serotonin (5-HT), which are indicative of neuronal toxicity. These depletions and the resulting toxicity can be attenuated pharmacologically or by lowering ambient temperature. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (DZ) blocks depletion of 5-HT induced by methamphetamine (METH) and p-chloroamphetamine (PCA), but not fenfluramine (FEN). This study investigated whether the effects of DZ and another calcium channel antagonist, dextromethorphan (DEX), are due to induction of hypothermia. Male Sprague-Dawley rats were injected with either saline (SAL), DZ (1 or 2 injections of 2.5 mg/kg), or DEX (75.0 mg/kg) followed by either SAL, METH (4 injections of 10.0 mg/kg), PCA (1 injection of 10.0 mg/kg) or FEN (2 or 4 injections of 12.5 mg/kg). Core body temperature (TEMP) was monitored for 4 h or longer with radiotelemetry. Base-line TEMP was between 37.0 and 37.6 degrees C. SAL/METH caused a significant increase in TEMP which peaked at 40.8 +/- 0.50 degrees C after the last injection. Coadministration of DZ with METH caused TEMP to decrease to 33.8 +/- 0.30 degrees C within 2 h of the first injection and lasting more than 3 h, and protected against depletion of 5-HT. SAL/PCA caused a small increase in TEMP to 37.7 +/- 0.36 degrees C, whereas coadministration of DZ with PCA decreased TEMP to 35.2 +/- 0.50 degrees C, lasting 2 h, in a dose regimen which has been shown to be neuroprotective.(ABSTRACT TRUNCATED AT 250 WORDS)

http://www.ncbi.nlm.nih.gov/pubmed/7853205

The abstract is cut short but you can see MK801 reduces body temperature, I'd be surprised if DXM didn't too. There's another study where DXM attenuates the hyperthermia induced by morphine. Usually NMDA antagonists lower body temperature.

 

[ebola?]

>>This is just speculation but maybe the sitution is that the atypical AD's increase 5-ht in a more indirect and downstream fashion than more traditional AD's. The downstream action could have a hard celling on 5-ht concentration increases because of its indirect activity, and thus not provide enough of an excess to put users in any danger when combined with MDMA. Where does Remeron bind?>>

Remeron is a weird one. "Mirtazapine acts as an antagonist at central presynaptic α2 adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. . .Mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors. Mirtazapine has no significant affinity for the 5-HT1A and 5-HT1B receptors." (From rxlist.com). Remeron also has a few other effects that are peripheral to this discussion. Thus, by blocking a subset of its own effects, remeron increases transmission at 5ht1 sites but not elsewhere. My pharmacology knowledge is insufficient to determine whether remeron's is a potent enough antagonist at 5ht2a sites to block classical psychedelics (I have done no bioassays on it personally), or to determine what factors limit this increase in serotonin.

ebola

 

[grue]

^I bet that the significant adrenergic antagonism would end up pretty much completely shutting down psychedelic activity downstream, even if it doesn't interfere with action at 5HT2a.

 

[ebola?]

really?
How so?

Is adrenergic modulation necessary for the vigorous function of circuits involving 5ht transmission (radiating from the pons, if I remember right)?

Do we know enough about what psychedelics do to say what neural circuits they involve?

ebola