i've for a long time pondered how the mechanisms behind the often reported "loss of magic" with mdma work. some time ago downregulation of serotonin receptors or the much discussed neurotoxicity seemed likely candidates.
but as neurotoxicity is pretty unlikely to occur when not dosing stupidly high (Buchert 2003, de Win 2006) and even if it does occur is reversible in up to 6 months (see references above) while loss of magic seems to be permanent in most people and takes upward of 6 months in most others (just anecdotal reports, don't have statistics on that...). also when neurotoxicity would be the cause then methylone shouldn't still have the magic (more on methylone later), so we'll leave that one out here.
5-HTR downregulation on the other hand also seems like an unlikely candidate for two reasons:
first we have the effects of mdma when the magic is lost. in me and my friends the effects of mdma have changed since losing the magic in such a way that we are more "smacked out", equally "fucked up", but get less drive and euphoria than before (may be different in areas where methamphetamine in pills is common). that sounds more akin to experience reports with mdai (sadly no experience with that one yet) than amphetamine, but with a reduced 5-HT-component one would expect that the effects would be more akin to straight stimulant.
the second thing is methylone (and mephedrone). lots of people report regaining the magic with methylone (me and my friends included) and there are reports of people mentioning mephedrone resembling their first experiences with mdma. but both methylone and mephedrone have a larger DA/NE component then 5-HT compared to mdma. one could object that throwing a dopamine releaser / reuptake inhibitor like cocaine or amphetamine into the mix should then bring the magic back, but cocaine seems to block mdma's effects by binding to SERT with a higher affinity and amphetamine probably does likewise (i have noticed completely abolished effects from mdma when combining with amphetamine, even when mdma still did it's magic and with a good dose of pure crystal).
so my hypothesis is that we don't get enough DA stimulus when having lost the magic from mdma. ways to test that would be to combine mdma with a selective DA releaser and hoping to get the magic back. but i don't know of any likely candidates as most selectively dopaminergic compounds (like methylphenidat or MDPV) seem to be reuptake inhibitors and i don't know if that would work. it might be worth a try.
another thing that could work would be combining mdma with the selective MAO B inhibitor selegiline which is mostly dopaminergic in action. there are reports of people combining selegiline and MDAI (low doses!) safely and getting mdma-like effects (MDAI Thread, PD).
Another possible explanation for loss of magic independent of DA and 5-HT could be oxytocin. but we don't have much information about that, neither if methylone actually causes release of oxytocin like mdma does (i would guess that it does) or if methylone releases oxytocin in a different manner than mdma does (otherwise you'd expect loss of magic with mdma to carry over to methylone). sadly we don't have any DA/5HT(/NE) releasers proven to be without oxytocin release to see if they have the magic.
what do you think about that? anything blatantly obvious that i have overseen?
but as neurotoxicity is pretty unlikely to occur when not dosing stupidly high (Buchert 2003, de Win 2006) and even if it does occur is reversible in up to 6 months (see references above) while loss of magic seems to be permanent in most people and takes upward of 6 months in most others (just anecdotal reports, don't have statistics on that...). also when neurotoxicity would be the cause then methylone shouldn't still have the magic (more on methylone later), so we'll leave that one out here.
5-HTR downregulation on the other hand also seems like an unlikely candidate for two reasons:
first we have the effects of mdma when the magic is lost. in me and my friends the effects of mdma have changed since losing the magic in such a way that we are more "smacked out", equally "fucked up", but get less drive and euphoria than before (may be different in areas where methamphetamine in pills is common). that sounds more akin to experience reports with mdai (sadly no experience with that one yet) than amphetamine, but with a reduced 5-HT-component one would expect that the effects would be more akin to straight stimulant.
the second thing is methylone (and mephedrone). lots of people report regaining the magic with methylone (me and my friends included) and there are reports of people mentioning mephedrone resembling their first experiences with mdma. but both methylone and mephedrone have a larger DA/NE component then 5-HT compared to mdma. one could object that throwing a dopamine releaser / reuptake inhibitor like cocaine or amphetamine into the mix should then bring the magic back, but cocaine seems to block mdma's effects by binding to SERT with a higher affinity and amphetamine probably does likewise (i have noticed completely abolished effects from mdma when combining with amphetamine, even when mdma still did it's magic and with a good dose of pure crystal).
so my hypothesis is that we don't get enough DA stimulus when having lost the magic from mdma. ways to test that would be to combine mdma with a selective DA releaser and hoping to get the magic back. but i don't know of any likely candidates as most selectively dopaminergic compounds (like methylphenidat or MDPV) seem to be reuptake inhibitors and i don't know if that would work. it might be worth a try.
another thing that could work would be combining mdma with the selective MAO B inhibitor selegiline which is mostly dopaminergic in action. there are reports of people combining selegiline and MDAI (low doses!) safely and getting mdma-like effects (MDAI Thread, PD).
Another possible explanation for loss of magic independent of DA and 5-HT could be oxytocin. but we don't have much information about that, neither if methylone actually causes release of oxytocin like mdma does (i would guess that it does) or if methylone releases oxytocin in a different manner than mdma does (otherwise you'd expect loss of magic with mdma to carry over to methylone). sadly we don't have any DA/5HT(/NE) releasers proven to be without oxytocin release to see if they have the magic.
what do you think about that? anything blatantly obvious that i have overseen?
