MDMA homologs selective serotonin-dopamine reuptake inhibitors/releasers

[paracelsius]

MDMA is a balanced Serotonin-Dopamine-Norepinephrine releaser (SDNRA). Selective serotonin-dopamine reuptake inhibitors (SDRI) and/or releasers (SDRA) are extremely rare. I mean, those drugs affecting DA and SERT but not Norepinephrine. In fact, only 2 compounds I know of have ever been reported with this selectivity profile: 5-chloro-alfa-methyl tryptamine (5-Chloro-αMT) which is a selective SDRA (possibly SDRI as well) and UW-101 aka alfa-cyclopropyl methylenedioxyphenethylamine (basically MDMA with the alfa methyl replaced by a cyclopropyl) which is a selective SDRI/A. It is extremely rare to see a selective SDRI/A that does not also affect NE, but correct me if I am wrong.

Now what would a selective SDRA be like? entactogen like MDMA without any physical stimulation or cocaine-like without MDMA entactogen. Or how about SDRI or the combination ie balanced selective SDRI and SDRA. Have yet to see any experiences with these and compounds with similar profile like above 2.

 

[dopamimetic]

What complicates the topic is that NE and DA are both metabolically coupled (DA -> NE) as well as the transporters aren't always selective (guess it's more NET also working on DA than the opposite, and reboxetine/atomoxetine were advertised with stuff like that parts of the brain lack DATs and there the NET also carries DA). Then the main difference will be whether you have a SDRA or a SDRI. The latter will be probably non-empathogenic and carry more side effects than pleasure (think of taking a high dose of venlafaxine / duloxetine without tolerance) - even pure 5HT releasers are very different from SSRIs. That e.g. methylphenidate is described as a NDRI is misleading, it was found to be an inverse agonist like cocaine, so causing reversal of the transporter leading to release just with a different pattern than the amphetamines.

So what you want are releasers. My halfway-educated guesses are that a pure SDRA would be, depending on the 5HT : DA, in the range as follows.

1. Mostly 5HT, little DA: mellow-happy, almost sedating/couch-locking compound with little entactogenia (little DA, like 5-AI; never done it personally though, or maybe roughly 5-MAPB with less push)
2. In-between: The empathogenic range
3. Mostly DA, little 5HT: mentally stimulating, hyperactive, euphoric - a non-physical coke. But as some of the released DA will end up as NE, you can't completely avoid physical stimulation with DRAs, then you'd need dopamine agonists. They might make an interesting combo, like 5-AI + hi dose memantine.

Can tell that low-dose/"plateau 1" DXM (being a potent SNRI which somehow can work acutely, in contrast to the antidepressants) together with a decent dose of memantine is pretty enjoyable. SSRIs don't come with full-on entactogenia but it's nice and pretty euphoric without any hangover.

You could do MDMA + clonidine "for science" Clonidine fools the body into believing the NE levels were higher than they actually are, lowering its release.

SDRI + SDRA would make an interesting experiment, for long I believed reuptake inhibitors to tendencially block the effects of releasers like some old sources mentioned but this has been revised and was wrong. A NDRI and methylphenidate would compete but not methylphenidate + amphetamine.

But what idea I personally like most is the use of a weak, reversible MAO inhibitor together with a lower strength SDRA. While it not only sounds dangerous but is, it can be done safely with caution -> 4,4'-DMAR did this, and I absolutely loved that compound when dosed low. An empathogen with an antidepressant afterglow - where else do you get this from? But this compound has vanished, and still need to find a fitting MAOI as even the RIMA (and for my mood absolutely useless) moclobemide caused strong BP increase with just 1-2mg d-amph. So a really selective SDRA would certainly help.

Goal of course would be to avoid transmitter depletion and crash.

 

[paracelsius]

..SDRI + SDRA would make an interesting experiment, for long I believed reuptake inhibitors to tendencially block the effects of releasers like some old sources mentioned but this has been revised and was wrong. A NDRI and methylphenidate would compete but not methylphenidate + amphetamine.

But what idea I personally like most is the use of a weak, reversible MAO inhibitor together with a lower strength SDRA. While it not only sounds dangerous but is, it can be done safely with caution -> 4,4'-DMAR did this, and I absolutely loved that compound when dosed low. An empathogen with an antidepressant afterglow - where else do you get this from? But this compound has vanished, and still need to find a fitting MAOI as even the RIMA (and for my mood absolutely useless) moclobemide caused strong BP increase with just 1-2mg d-amph. So a really selective SDRA would certainly help.

Goal of course would be to avoid transmitter depletion and crash.

Very interesting. There is only ONE such compound afaik which has been described as both SDRA and SDRI and that's 5-Chloro-Alfa-Methyl-Tryptamine. it is less well known than the parent unsubstituted tryptamine aMT and I suspect aMT has somewhat similar profile. But those 2 are also 5HT2a/c and 5HT1a agonists and MAOIs..

α-Methyltryptamine (abbreviated as αMT, AMT) is a psychedelic, stimulant, and entactogen drug of the tryptamine class.[2][3] It was originally developed as an antidepressant by workers at Upjohn in the 1960s,[4] and was used briefly as an antidepressant in Russia under the trade name Indopan before being discontinued. via wiki

With Aminorex, 4-MAR and 4,4'-DMAR it is a different story altogether. Quite fascinating little kept secret gems of stims! (guess thats why DEA are coming them!!!) As I mentioned in another thread, they have the most interesting profile I've seen which make them quite unique among stim/entactogens: selective NDRI v 5-HT AND at the same time selective SDRA v DA and NET all with EC50 within the same range so rather interesting balance.. I'll post some SAR data on those later (am still digging out old studies ..