Another theory is that it is a metabolite produced from the MDMA which is causing the damage. But that would still need to suggest that the metabolite has an affinity for the receptor.
You're thinking of the serotonin transporter, not receptors. At any rate, it's actually not surprising that a metabolite would have affinities similar to it's parent chemical; single metabolic steps usually don't change structure by all that much (such as MDMA -> MDA.) The metabolite would have different properties, but not necessarily much different.
and perhaps a new MDMA molecule attaching to an exhausted receptor produces the effect of damaging it (or rendering it unable to respond to future MDMA exposure until it has returned to its baseline).
What we know more or less 'for sure' about MDMA neurotoxicity is that
something (MDMA or an MDMA metabolite or ?) is:
1. Drawn into the serotonin axon by the serotonin transporters (SERTs).
2. Broken down by the MAO enzyme, creating oxidizing chemicals.
3. These oxidizing chemicals are capable of damaging the axon if not neutralized by antioxidants or other protective mechanisms.
Re the original topic:
Downregulation of serotonin receptors is due to over-activation, which in turn would be caused by elevated serotonin levels in the synaptic cleft (the space between two neurons.) Since an SSRI would, by interfering with MDMA, actually cause a reduction in the amount of 'free' serotonin (which would in turn reduce how often the receptors were being activated) VelocideX suggests that taking an SSRI shortly after using MDMA might reduce the extent of receptor over-activation, thus reducing the extent of downregulation.
The idea seems quite reasonable in theory, although in practice there may be little real benefit because the effect could be very small.
Although blood levels of MDMA are certainly a starting point for predicting effects, there are other cycles at work, notably the loss of serotonin from the axons during MDMA exposure (both from metabolic breakdown as well as simple diffusion away from the axon.) Because of this, MDMA's effects would likely actually wind down more quickly then blood levels of the drug alone would suggest; the amount of serotonin being released and kept in the synapse would be a function of both MDMA concentration within the brain
and remaining reserves of serotonin within the serotonin axons, and both variables would decline with time.
Also riding on the coattails of drug levels is downregulation itself. I couldn't tell you what the mechanism is, but it's no doubt a 'collective' mechanism (the neuron cares about how many total receptor activations/sec it's getting; it can't tell/doesn't care how often a specific receptor is being activated.) If a neuron 'wants' 50 activations a second, it doesn't care if that comes from 50 receptors each being activated once, or one receptor being activated fifty times...it's all the same to it. The point being that, once downregulation has begun (and it probably starts to happen fairly quickly) to reduce the number of available receptors, then the number of activations will also go down, reducing the motivation for the neuron to produce further adaptations even if there is still a ton of serotonin floating around.
So, downregulation is a factor of drug concentration, serotonin concentration, and available receptor density, all of which are declining during the MDMA high. There's also going to be some threshold level of receptor activation at which downregulation should no longer occur, making the low-drug concentration tail end of the high less significant than the high-concentration early phase. As a result, I would expect a much sooner 'crash' in the cycle of downregulation than MDMA levels alone would indicate. It's an interesting idea, and as I say, not unreasonable...but the effect of taking an SSRI after MDMA may have very little actual effect on the extent of receptor downregulation.
![:\](https://bluelight.org/xf/BL_Images/Orig_Emoji/wrygrin.gif "wry grin :\")
