Pharmacology Dimethyl-MDMA

[red22]

Recent clinical evidence suggests that racemic 3,4-methylenedioxymethamphetamine (MDMA) might be useful for treating a range of neuropsychiatric diseases including post-traumatic stress disorder (PTSD) and depression. However, concerns about its abuse potential stemming from its monoamine releasing properties have hampered its clinical development. Thus, safer analogues of racemic MDMA with comparable therapeutic effects are highly desirable. Here, we compare the pharmacological effects of MDMA enantiomers with those of its methylated analogue 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA). We found that R-MDDMA did not directly activate 5-HT2B receptors, induce serotonin efflux, produce a head-twitch response, impact body temperature, or induce hyperlocomotion at therapeutically relevant doses. However, it still promoted structural neuroplasticity in cortical neurons, facilitated fear extinction learning, and produced sustained antidepressant-like effects. Taken together, our results suggest that R-MDDMA might be a safer MDMA analogue with similar therapeutic properties.

R-MDDMA is a Safer Analogue of MDMA with Therapeutic Potential. Vargas, M. V., Hatzipantelis, C. J., Dunlap, L. E., Tombari, R. J., Avanes, A. A., Vaillancourt, S., Llorach, P., Salgado, J. S., Heifets, B. D., Olson, D. E. 2026. ACS Chemical Neuroscience, XXXX, XXX, XXX-XXX https://pubs.acs.org/doi/abs/10.1021/acschemneuro.5c00891

Thanks to Julie Holland, she always posts new psychedelic research in her twitter feed: h‍ttps://x.com/BellevueDoc/status/2050566806138421332

 

[4DQSAR]

The human body sequentially N-dementylates. Rodents can metabolise in different ways. In man, I would expect at least some MDMA and thence to MDA to turn up.

 

[Smyth2]

A case I have been looking at recently is how CTDP-30,640 is metabolized by demethylation pathway into indatraline. Even though it has some mild activity prior to metabolization (particularly at the SERT), it is described as a prodrug. Interestingly though, Lu-17-133 is a very potent NDRI so the SAR is not as simple as to conclude that no steric bulk can be tolerated about the nitrogen position.

I would say with MDDMA a competing pathway is going to be demethylation of the methylenedioxy bridge as this is easily digested.

 

[4DQSAR]

Indeed, the human liver doesn't get the credit it deserves in protecting us from abusing our bodies and so many competing enzymes all acting in concert.

I used just two tricks and they always seemed to work.

1)Sacrificial moiety i.e. something that non-specific blood enzymes will oxidize the heck out of, gloconate and gone or
2)Chuck out ADME and go for ADRE.

Yes, I know it sounds odd as that isn't what we were taught, but look closer and a surprisingly large number of medicines use the above.

 

[Smyth2]

It's interesting they use the term "psychoplastogen" to describe the effects of MDMA whereas alot of sources say that it is a neurotoxin.

It's interesting since depending by what you call it it could be made to sound like a medicine or a poison.

I recently came across a novel alkaloid called Clausenamide that is likewise described as psychoplastogenic.

 

[4DQSAR]

There are a few compounds described as being "psychoplastogens" that are not psychedelic or entactogenic. But it still seems like an observed action rather than being associated with one target.

It's also one of those things I suspect we will see the pharmactucical industry using for indication creed as we have with ketamine. I think the MXE patent is about to run out but EXE is active and yet to be patented (as far as I know). Even then, one can obtain a patent for a specific USE hence this huge rush to patent EVERY psychedelic.

But oddly NOT 7-substituted tryptamines. Why? Likely because Upjohn got there first - but, again, is antidepressant and neuroplastogen a different thing from a legal perspective? Pfizer will certainly tax anyone seeking to use a 7-methyl indole and that may be why they didn't rush to patent - even expired, it would be hard to claim a new utility if someone contested the point - but Pfizer seems unlikely to take Pfizer to court. Neat.

 

[fuckabout89]

Recent clinical evidence suggests that racemic 3,4-methylenedioxymethamphetamine (MDMA) might be useful for treating a range of neuropsychiatric diseases including post-traumatic stress disorder (PTSD) and depression. However, concerns about its abuse potential stemming from its monoamine releasing properties have hampered its clinical development. Thus, safer analogues of racemic MDMA with comparable therapeutic effects are highly desirable. Here, we compare the pharmacological effects of MDMA enantiomers with those of its methylated analogue 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA). We found that R-MDDMA did not directly activate 5-HT2B receptors, induce serotonin efflux, produce a head-twitch response, impact body temperature, or induce hyperlocomotion at therapeutically relevant doses. However, it still promoted structural neuroplasticity in cortical neurons, facilitated fear extinction learning, and produced sustained antidepressant-like effects. Taken together, our results suggest that R-MDDMA might be a safer MDMA analogue with similar therapeutic properties.

R-MDDMA is a Safer Analogue of MDMA with Therapeutic Potential. Vargas, M. V., Hatzipantelis, C. J., Dunlap, L. E., Tombari, R. J., Avanes, A. A., Vaillancourt, S., Llorach, P., Salgado, J. S., Heifets, B. D., Olson, D. E. 2026. ACS Chemical Neuroscience, XXXX, XXX, XXX-XXX https://pubs.acs.org/doi/abs/10.1021/acschemneuro.5c00891

Thanks to Julie Holland, she always posts new psychedelic research in her twitter feed: h‍ttps://x.com/BellevueDoc/status/2050566806138421332

Who the fuck wants MDMA and LSD without the high

 

[BadBoy377]

Who the fuck wants MDMA and LSD without the high

People with debilitating psychiatric disorders.

 

[fuckabout89]

People with debilitating psychiatric disorders.

I know lol, you get my point. They gotta take the fun out of it.

 

[Ki3ly]

The Brain's Chemistry: Both MDMA and LSD alter neurotransmitter activity (like serotonin and dopamine),
shifting how the brain processes emotion, memory, and perception.

Clinical trials carefully monitor in therapeutic settings.

MDMA: Used primarily alongside therapy without overwhelming fear or negative emotions.

LSD: Investigated for conditions like anxiety and severe depression and helping patients re-contextualize.



Uhh. Oh. Yes they can.

 

[BadBoy377]

I know lol, you get my point. They gotta take the fun out of it.

I do, I do, mate.

Cannae deny it's a good answer though.

Trips are always more rewarding when there's a degree of discomfort I think. It's like the trauma n negativity leaving you.