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I'm not sure if I understand the synergetic effects of MDMA and SSRIs correctly.

According to PMC81503 "It is clear, however, that the increase in the net release of serotonin (and possibly dopamine) is the major mechanism of action underlying the distinctive mental effects of MDMA" but it also states "MDMA does not act by directly releasing serotonin but, rather, by binding to, and thus blocking, the transporter involved in its reuptake."

Do SSRIs interfere with MDMA? Do both bind to SERT, do they compete? Do SSRIs prevent the serotonin released by MDMA from being reuptaken? Do SSRIs increase the net release of MDMA when taken together compared to MDMA alone?

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Do SSRIs interfere with MDMA? Yes, a 2022 systematic review by Saparast et al found that SSRIs and duloxetine attenuated the subjective effects of MDMA.

Do they both bind to SERT? Yes, but they act slightly differently. From the same systematic review, MDMA results increases neurotransmitter levels in the synaptic cleft by reversing their transport and promoting their release, while antidepressants do so by preventing the reabsorption (reuptake) of these neurotransmitters, thereby increasing their availability in the synaptic cleft.

Do SSRIs prevent the serotonin released by MDMA from being reuptaken (sic)? Theoretically, I think they would. However, things can get very complicated at both pharmacokinetic and pharmacodynamic levels and I'm not aware of a study that has demonstrated this finding.

Do SSRIs increase the net release of MDMA when taken together compared to MDMA alone? Theoretically, yes. Further, some SSRIs are inhibitors of the cytochrome P450 enzyme CYP2D6 which breaks down MDMA. So you would expect higher plasma concentrations. However, this doesn't accord with the results of studies showing that individuals taking SSRIs had attenuated subjective effects from MDMA.

There's limited literature on this topic and it's challenging to extrapolate from small studies of volunteers.

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  • $\begingroup$ I think, given the time it takes for SSRIs to kick in, that the answer to this Q depends a lot on how long the SSRIs have been used at the time the MDMA is taken. $\endgroup$
    – AliceD
    Commented Jan 9 at 11:40
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    $\begingroup$ This is good point. Most of the studies included in the review I cited either coadministered SSRIs and MDMA or had subjects on antidepressants for only a few days before MDMA administration. This is probably not sufficient time for 5HT1A desensitisation and increase in the expression of BDNF & TrkB. Given MDMA is topical, I'm sure there'll be a study of its effects in those on long-term SSRIs before too long, if it hasn't already been done. $\endgroup$ Commented Jan 10 at 2:15
  • $\begingroup$ In the context of the question I presumed a steady state of SSRI levels. I guess what's more relevant are SSRIs long term effects on 5HT. I'm not sure if desensitisation would happen if SSRIs balance a natural deficit of serotonin availability. I'd guess that normalized serotonin levels don't oversaturate 5HT and 5HT would rather upregulate without SSRIs. - Anecdotally I can say two things. LT SSRI use prolongs the effect of MDMA by 50-100%. They also eliminate any adverse after-effects of mdmas serotonin depletion (mdma hangover). So I'm looking for sources which affirm these claims. $\endgroup$ Commented Jan 14 at 10:22
  • $\begingroup$ I guess the danger of combining these two substances would be an overdose of either them which could potentially lead to serotonin syndrom which would be kept up by SSRIs and AFAIK there's no possibility to flush it out with a neutral antagonist, so you would have to stop use of SSRIs to allow normal recycling of serotonin. $\endgroup$ Commented Jan 14 at 10:26
  • $\begingroup$ SSRIs don't correct any "deficit of serotonin availability" - see nature.com/articles/s41380-022-01661-0. A lot of these drug effects are, in part, due to placebo effects so I wouldn't rely on anecdotal experience to infer anything about what's happening at a neurochemical level. $\endgroup$ Commented Jan 14 at 11:51

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