The evidence is definitive re: serotonin synthesis and recovery.
VMAT2 inhibition is a vital mechanism for amphetamine/MDMA induced neurotransmitter efflux, the way VMAT2 inhibition works is by interfering with the transport of neurotransmitters into the vesicles, causing cytosolic levels of 5-HT to rise (the 5-HT is then transported out of the cytosol via a reverse conformation SERT). Vesicular depletion is seen with VMAT2 inhibtion. If MDMA wasn't causing depletion of synaptic levels of 5-HT starting during some timeframe about 3 hours after administration (Where SSRI administration is still neuroprotective), there really wouldn't be uptake of harmful molecules in the nerve terminal via SERT that can be prevented with 5-HTP administration (see Nichols study below). The idea is that the deficit of 5-HT means that there is decreased competition for access to the SERT, so other molecules can gain access during whatever timeframe there are lower 5-HT levels with higher levels of harmful molecules.
https://www.ncbi.nlm.nih.gov/pubmed/16835371/ - "Second, our data strongly suggest that amphetamine-type agents deplete vesicular neurotransmitter via a carrier-mediated exchange mechanism"
http://onlinelibrary.wiley.com/doi/...ionid=AE2D45703D4177D327A64AE5CF540CFE.f03t03 - "Depletion of vesicular 5-HT, by inhibition of vesicular monoamine transporter type 2 with tetrabenazine prevented the release. Thus although the SERT reversal contributes,
a direct vesicle-depleting action is essential for MDMA release of 5-HT."
https://www.ncbi.nlm.nih.gov/pubmed/7934616 (Nichols) - "Attenuation of 3,4-methylenedioxymethamphetamine (MDMA) induced neurotoxicity with the serotonin precursors tryptophan and 5-hydroxytryptophan." "These results suggest that
depletion of 5-HT stores is important for MDMA-induced neurotoxicity. The possible significance of this 5-HT depletion in MDMA-induced serotonergic terminal degeneration is also discussed."
As far as receptor densities -- they are using a surrogate way to measure receptor density -- not a direct measurement -- binding affinity could be affected, causing lower binding and making it SEEM like there are lower densities.
Regardless, there is no established populational mean and SD for serotonin levels, receptor densities, etc in the general human population.
Furthermore, the fact that diet, herbs, and other factors can directly and acutely affect receptor endocytosis through the beta arrestin/dynamin pathway -- it is bad science to lay surrogate determined receptor density deltas solely at the feet of MDMA use.
Radioligands are used all the time to determine receptor expression and affinity, yes radioligand binding assays are not completely direct but they are still very useful, and 5-HT2A upregulation is still a useful marker to detect whether or not there is decreased 5-HT release. In this case upregulation of occipital cortex 5-HT2A in abstinent MDMA users has been seen in 2 different studies now that I'm aware of.
5-HT2A upregulation is a known consequence of decreased 5-HT release, acutely decreased 5-HT2A via downregulation after use of a drug that releases serotonin en masse is not surprising and is a good explanation for why decreased 5-HT2A is observed in people recently using MDMA. When you say "binding affinity could be affected", this still implies that there are functional consequences to MDMA use, and regardless of whether 5-HT2A/D2 heterodimers etc are forming with acute use, that scenario still agrees with my notion that there are changes that occur with recent MDMA use and its probably best to
spread your use out and not use tons every single weekend.
Saying something akin to "Something about the MDMA users recent behavior caused apparently lower 5-HT2A expression and we're not sure if its MDMA" doesn't make sense in the context of use of a SRA. Why bother trying to explain away acute downregulation of 5-HT2A with things like diet when they just used a serotonin releasing agent? You really think diet is going to be more important in determining 5-HT2A expression than whether or not they just used MDMA?
Individuals with normally low receptor densities may be pre-disposed to use MDMA.
Extrapolating axonal damage and other neurotoxic effects seen in animal models of MDMA overdose to human recreational use is ALSO BAD SCIENCE.
Pre-existing low 5-HT2A receptor expression doesn't explain why 5-HT2A expression in MDMA users that have been abstinent is actually measured to be
higher than recent users and controls.
I'm not extrapolating to general human recreational use and
certainly not responsible psychotherapeutic use, I'm concerned with severe adolescent abuse in populations predisposed to neuropsychiatric/neurodegenerative disease. We don't have long term data (Even though this thread is about a long term user having issues) so I'm suggesting we remain skeptic and cautious. I've said repeatedly the evidence is not conclusive either way, and that the harm-reductionist stance is to err on the side of caution, instead of acting like weekly abuse of MDMA for decades will have zero consequences for all people.
The literature is littered with cancer treatments and other investigational medications that cure rodents/primates -- yet are non or poorly functional in human.
That's why empirical evidence and the peer review process is so important - we need more empirical evidence and longitudinal studies before we can make any conclusions. Until then I remain skeptic and I suggest you do too. The case reports of neuropsychiatric disease after MDMA go back as far as the 1980s. "Post LSD visual syndrome" has been recognized for a long time as well, and many people have reported HPPD from MDMA. Its also been recognized in the literature by one study in particular that MDMA can cause HPPD
https://www.ncbi.nlm.nih.gov/pubmed/24933532
I understand there is poor quality evidence in support of some treatments, but I'm not saying "
Go do this cancer treatment even though we don't know the risks", I'm saying "
Don't do too much MDMA because we don't know the risks", its the completely inverse principle. Although I should point out that enough people have anecdotally reported adverse effects from MDMA that we know it has some risks. That doesn't mean it will happen to every person.
