More discussion of the clinical effects of MDMA on 5-HT neurons

MDMA causes a short-term release of 5-HT from the neuron. MDMA blocks both the reuptake pump from the synapse into the neuron, and the pump into the synaptic vesicles. It also causes the release of 5-HT from the synaptic vesicles and a release of 5-HT out of the neuron. Because of this action, it tends to flood the synapse with serotonin in the short-term. In the long-term, the 5-HT which is outside of the vesicles can be broken down by metabolic enzymes like MAO, and following treatment with MDMA there will be a downswing in the availability of 5-HT. That's why tryptophan-containing foods like milk and bananas are a good idea after MDMA in order to help to replenish 5-HT.

The McCann-Ricaurte study actually wasn't looking at 5-HT levels, but the binding of a radioactive tracer chemical to the 5-HT reuptake sites in the brain. If, as the authors would like to theorize, there is a narrowly defined range of number of 5-HT reuptake sites per neuron, then a reduction in 5-HT reuptake sites should correspond to a reduction in 5-HT neurons. Unfortunately, they entirely ignored the research showing that proven non-neurotoxic drugs like SSRIs, imipramine and tianeptine (a serotonin-specific reuptake stimulanting drug) all cause decreases in 5-HT reuptake densities and in gene expression of 5-HT reuptake pump mRNA suggesting that there are regulatory mechanisms operating at the gene level. Therefore, one pretty much expects that MDMA would similarly cause regulation of 5-HT sites in the absence of any neurotoxicity, and pretty much eliminates this whole approach to assessing MDMA neurotoxicity as being flawed.

Furthermore, the study found that the highest dosing MDMA users still had 5-HT transporter levels that were the same as the low end of the control non-MDMA using subjects. The fact that there were control subjects with 5-HT transporter levels which were as low as the MDMA subjects suggests that there might be selection effects at work particularly as these were subjects that had taken some 200+ doses of MDMA at an average does of over 300mg at a time. It's possible that low transporter levels lead to this pattern of MDMA use and not the other way around.

Other studies have shown that MDMA users have lower levels of 5-HIAA, which is a 5-HT metabolite (and low levels of 5-HIAA and 5-HT have been correlated in monkeys). However, this ignores evidence in monkeys that MDMA can cause transient and substantial decreases in 5-HT and 5-HIAA in the absence of any decreases in binding to the 5-HT transporter (and hence, in the absence of any neurotoxicity). Furthermore, the effect on MDMA users' sleep and psychology has been shown to be generally the opposite of what one would expect as a result of lesioning the 5-HT system. Of course the fact that a statistically significant effect was found to occur in the sleep of MDMA users (and one which probably increased sleep quality overall, nothing which could be interpreted as damage) was claimed to be evidence of possible "damage" by the study's authors never mind that the results were 180 degrees away from what was predicted.

I think that MDMA definitely knocks your serotonin system around and therefore it's not a good idea to do it a lot. Personally, I feel after-effects for about a week. This is not, however, evidence of neurotoxicity. Similar after-effects have been described for cocaine, which is neurochemically very similar to MDMA, only it preferentially does to dopamine neurons what MDMA preferentially does to serotonin neurons (although there's overlap and effects of MDMA on dopamine, and effects of cocaine on serotonin). Cocaine is also not a neurotoxin.