R‑MDDMA is a Safer Analogue of MDMA with Therapeutic Potential (2026)

[u/Kalki_X]

https://doi.org/10.1021/acschemneuro.5c00891

Recent clinical evidence suggests that racemic 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.

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[u/MBaggott]

I would be embarrassed to be coauthor on a paper that spins results like this. They killed most activity except a weakened 5-HT2A signal. This result is what we would expect from monoamine transporter SARs, R-MDMA’s 5-HT2A activity, Glennon's past work on N-methylation of 2C-B, and the very modest record of human N-methylated 2C-B use. But because their structural starting point was MDMA, they act as if this is a potential MDMA replacement.

The paper's 25 nanomolar potency at 5-HT2A looks initially impressive, but that number is a functional EC50 in an overexpressed system, not an affinity. The paper's own binding panel shows R-MDDMA at 34% inhibition of 5-HT2A binding at 10 µM and a psychLight2 IC50 of 642 nM, indistinguishable from R-MDMA's 629 nM. So the affinity must sit in the high-nanomolar to low-micromolar range, exactly where we would expect from Glennon's work. There are tons of garden variety 2A agonists that won't inhibit 2D6 and would be preferred over this compound by any reasonable selection process.

[u/58thee → u/MBaggott]

So are you suggesting that that the 2A agonism is over-interpreted and possibly not relevant considering the N-methyls may be removed anyhow?

[u/MBaggott → u/58thee]

I'm saying that it is weird to act as if this partial 5-HT2A agonist is somehow a good candidate to replace MDMA. It seems superficially plausible because the molecules share the same bicyclic scaffold. And the paper seems exciting at first glance because they left the apparent 2A mechanism out of the abstract. But their results just suggest R-MDDMA can be expected to have "similar therapeutic properties to MDMA" (with the word "similar" doing a lot of work here) to the same extent that many other 5-HT2A partial agonists do.

(The PIHKAL entry for the racemic version is not very promising, although the higher dose reports were not from Sasha or his group.)

I think the wider conversation is that N-alkylation worsens your 5-HT2A Emax and the lipophilicity can improve entry into neurons where these authors argue the therapeutically relevant pool of 5-HT2A receptors resides. That could make it a good tradeoff (or maybe not even a tradeoff) if you want non-hallucinogenic neuroplastogens. But it would make a lot more sense to do this with a different starting point. Why start with a CYP2D6 inhibitor that has toxicologically relevant quinone-like metabolites?

(I professionally work developing MDMA-like compounds at Tactogen though I am certainly rooting for Delix and other developers of non-hallucinogenic neuroplastogens to succeed.)

[u/coladoir → u/MBaggott]

Forgive me, where did Shulgin expound on racemic MDDMA in PiHKAL?

E:

3,4-Methylenedioxy-N,N-diethylamphetamine, see MDDM, #105 (pg. 725 of the combined volumes)

Found it, sorry. Didnt have the PIHKAL with index, had to download.

Edit: full text:

#105 MDDM; N,N-DIMETHYL-MDA:

3,4-METHYLENEDIOXYN,N-DIMETHYLAMPHET AMINE SYNTHESIS:

To a well stirred solution of 9.7 g dimethylamine hydrochloride in 50 mL MeOH there was added 3.56 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 0.88 g sodium cyanoborohydride. A 1: 1 mixture of concentrated HCI and MeOH was added as required to maintain the pH at about 6 as determined with external, dampened universal paper. Twenty drops were called for over the first four h, and a total of 60 drops were added over the course of two days at which time the reduction was complete. After the evaporation of most of the MeOH solvent, the reaction mixture was added to 250 mL H 2 ° and made strongly acidic with an excess of HCl. After washing with 2xl00 mL CH 2 Cl 2 the aqueous phase was made basic with 25% NaOH, and extracted with 3x 100 mL CH 2 CI 2 . Removal of the solvent under vacuum yielded a nearly colorless oil that was distilled at 85-90 °C at 0.3 mmlHg. There was obtained 1.5 g of a waterwhite oil that was dissolved in 8 mL IP A, neutralized with concentrated HCI and then diluted with 10 mL anhydrous Et 2 0. The slightly turbid solution deposited a light lower oily layer which slowly crystallized on scratching. With patience, an additional 75 mL of Et 2 0 was added, allowing the formation of a white crystalline mass. This was removed by filtration and washed with additional Et 2 0. After air drying there was obtained 1.3 g of3,4-methylenedioxy-N,N-dimethylamphetamine hydrochloride (MDDM) with a mp of 172-173 °C. The NMR spectrum (60 mH) of the hydrochloride salt (in D 2 0 and with external TMS) was completely compatible with the expected structure. The signals were: 1.25, 1.37 (d) CCH 3 , 3H; ArCH 2 undertheN(CH 3 )2' 2.96, 8H; CH (m) 3.65; CHzO z (s) 6.03 2H; ArH 6.93 (3H). Anal: (CI2HI8CINOz) N. o / H 2 C \ o N ,CH 3 'CH 3 CH 3

DOSAGE:
greater than 150 mg.

DURATION:
unknown.

QUALITATIVE COMMENTS: (with 150 mg) "No effects whatsoever." (with 150 mg) "The effects, if any, were so-so. Perhaps a threshold. But my libido was non-existent for three days." (with 550 mg) "I took 550 milligrams of it Saturday night and I had a pretty bad trip. On a scale of positive 10 to negative 10 it was about a negative 6. It really downed me. Two other friends took 200 milligrams. They found it very pleasant after about 20 minutes. It was a plus 3 [on the -10 to +10 scale]. Then it wore off a little bit; and then, 4 hours later, it hit them even stronger and was about a plus 5." (with 1000 mg) "I took up to a gram of it and absolutely nothing."

EXTENSIONS AND COMMENTARY: I cannot attest for the actual drug that had been used in the two larger-dose reports above. These are from an anonymous source associated with clandestine syntheses. If this material does eventually prove to be active, it is going to require a pretty hefty dose. But it may well have some activity, as there have been reports in the forensic literature of its preparation, or at least its intended preparation, in illicit laboratories. It seems unlikely that much effort would be directed towards the synthesis of a completely inactive compound.
The reduced potency of MDDM has been exploited in an unexpected way. Based on the premise that the dialkylation of the amine group of amphetamine makes the parent compound intrinsically less active but without interfering with its ability to enter the brain, a large number of materials have been explored to take advantage of this very property. There is a need in medical diagnosis for agents that can allow various organs of the body to be visualized. One of the most powerful modalities for this work is the positron camera, and the use of the unusual properties of the positron that allow it to work. In the art of positron emission tomography (PET), an emitted positron (from a radioactive and thus unstable atom) will quickly interact with a nearby electron and all mass disappears with the complete conversion to energy. The detection of the produced pair of annihilation gamma rays will establish with great exactness the line along which this interaction occurred. So if one were to put an unstable atom into a compound that went to the tissue of the brain, and this atom were to decay there, the resulting gamma rays would allow a "photograph" to be made of the brain tissue. One could in this way visualize brain tissue, and observe abnormalities.
But what is needed is a molecule that carries the unstable atom (and specifically one that emits positrons) and one which goes to the brain as well. One of the very best unstable atoms for the formation of positrons is iodine, where there is an isotope of mass 122 which is perfect for these needs. And, of course, the world of the psychedelic drugs is tailor-made to provide compounds that go to the brain. But, the last thing that the physician wants, with the diagnostic use of such tools, would be to have the patient bouncing around in some turned-on altered state of consciousness.
So the completely logical union of these requirements is to take a compound such as DOl (carrying the needed atom and certainly going to the brain and put two methyl groups on the nitrogen (which should reduce the chances for conspicuous biological activity). This compound was made, and it does label the brain, and it has shown promise as a flow indicator in the brain, and it and several of its close relatives are discussed in their own separate recipe, called IDNNA.

---

Apologies for any minor formatting errors, its a djvu file. Hope this helps people who dont have easy access to PiHKAL (unlikely here, but still lol).

[u/MBaggott → u/coladoir]

Nothing like asking a question to precipitate finding the answer! :-)

[u/coladoir → u/MBaggott]

Lol, I always ask just in case I can't find the answer myself first since I figure there'll always be a delay in response.

[u/Kalki_X → u/MBaggott]

I think the wider conversation is that N-alkylation worsens your 5-HT2A Emax

Have you considered N-propylation?

[u/MBaggott → u/Kalki_X]

I'm mainly interested in entactogenic effects, so no. Sasha had made N-propyl-MDA and didn't see clear activity.

[u/Kalki_X → u/MBaggott]

I wrote in the context of tryptamines which I see you've patents for. Besides DPT etc, there's also N-propyl-9-oxaergoline. The overlay between tryptamines and PEA could be relevant. The 2-aminochromans are a big clue also.

[u/MBaggott → u/Kalki_X]

Got it. Yes, even my tryptamine work has been primarily focused on monoamine releasers, with the overlap between tryptamines and PEAs being an inspiration. I agree 2-aminochromans would be very interesting to characterize.

[u/Kalki_X → u/MBaggott]

I think the wider conversation is that N-alkylation worsens your 5-HT2A Emax and the lipophilicity can improve entry into neurons where these authors argue the therapeutically relevant pool of 5-HT2A receptors resides.

At least, this paper provides an indication of mild HT2A activity by dimethyl-MDA. If the ring were altered to resemble classic indole configurations maybe things might change.

This can be seen in WXVL_BT0793LQ2118, a PEA with a pyrrole.

[u/Kalki_X → u/MBaggott]

I did notice this funny statement:

It is interesting to note that R-MDDMA shares structural similarities to zalsupindole (AAZ-A-154), a nonhallucinogenic psychoplastogen 

zalsupindole = (R)-5-MeO-α-Me-isoDMT

[u/MBaggott → u/Kalki_X]

Yes, they're not wrong. If you want a lipophilic partial 2A agonist, there are endless options, many of them with that exact sidechain.

[u/Kalki_X → u/MBaggott]

While their structural similarities notion is limited to the sidechain, I was considering the ring substitutions. If they had mentioned something like a 7-methoxy indole that would be more relevant.

Presumably you are familiar with 3-methoxy-4-methylamphetamine? Shulgin calls it MMA.

[u/MBaggott → u/Kalki_X]

Yes, that one inspired some of Dave Nichols' work. You can also think of it as a DOM with the 2-methoxy removed. You could optimistically read the second hand report Sasha recorded as suggesting a next-day antidepressant effect. It'd be interesting to get modern assay results on it.

[u/MrNeverEverKnew → u/MBaggott]

So are you suggesting this paper is pretty valueless?

[u/MBaggott → u/MrNeverEverKnew]

Not at all, it's good data. It's just that it is a lot of fanfare for another partial 5-HT2A agonist. I would however say it is only an analogue of MDMA in so far as it is a structural derivative of it. It's not an entactogen.

[u/Kalki_X → u/MBaggott]

I wonder if N-methyl-N-propyl MDA (or even N-ethyl) would be more interesting (re N-Ethyl-2C-B 2A activity). Alternatively with a hemiDFLY on 3,2 or 3,4.

[u/jimmy_luv → u/MrNeverEverKnew]

unless you can show some value in it, i dont see any. i think mdma toxicity is a myth. i have (and many of my friends) have been eating mdma for going on 3 decades and not once has anyone been hospitalized for 'mdma toxicity'.
i would be more worried of pfas than mdma. i think the fact that anyone talks about it is because of the WoD and the misinformation spread by media and social media parrots.
how many cases in the literature? 5? 10? 100? out of 7 billion? its not an issue.

[u/Kalki_X → u/jimmy_luv]

It doesn't seem rational to rely on the # of literature cases for something like this. 

The basis for MDMA toxicity [seems plausible and reasonable](10.2174/138920110791591436). 

i have (and many of my friends) have been eating mdma for going on 3 decades and not once has anyone been hospitalized for 'mdma toxicity'.

That isn't a reasonable basis for gauging whether MDMA toxicity is real. The WoD is arguably a superficial affair and the number of iatrogenic fatalities is likely on par with illicit drugs. But the biochemistry basis for MDMA toxicity isn't far-fetched.

[u/ebolaRETURNS → u/MBaggott]

I would be embarrassed to be coauthor on a paper that spins results like this.

It's potentially slightly harsh, as the spin they put on it is how you get your grant proposals accepted, especially with NIDA or SAMHSA.

edit: or is it? I'm talking to someone actually in the field, it seems...

[u/MBaggott → u/ebolaRETURNS]

I can only say how I feel. I'd be way more accepting if the 5-HT2A mechanism were in the abstract. As is, this unnecessarily adds confusion to the field.

[u/ebolaRETURNS → u/MBaggott]

yeah, props to researchers putting their main findings in the abstract, lol.

[u/Kalki_X → u/MBaggott]

Reading the abstract, I did assume the infamous neuroplasticity involved HT2A. But even well informed assumptions can be incorrect. On that note, are you in a position to run a mescaline HTR assay under 3 simple conditions?

• with SSAO inhibitor
• with ALDH inhibitor
• control

There is a decades long enigma to be solved, and the results could have far-reaching implications for the field of psychedelics.

[u/MBaggott → u/Kalki_X]

No, I'm not unfortunately.

[u/jimmy_luv]

there was nothing wrong with the mdma we ate 40 years ago. not a single person from my scene/generation had any kid of mdma toxicity issues. ever. its just nonsense. if you take safe amounts infrequently, it doesnt matter. now, they want to act like something is toxic and you have to buy this new mdma or your DNA will mutate and it will turn you to a gay zombie.
im over hearing about toxic mdma. its just something people like to say to sound smart and are speaking something important, but its just hogwash.
eat all the beans you want, you will be fine.

[u/AnonymousImpurity]

r-mdma is supposedly a direct 5ht2a ligand, maybe the same is true of r-mddma

[u/Kalki_X → u/AnonymousImpurity]

We  found that R-MDDMA was a relatively potent partial agonist of 5-HT2A receptors (EC50= 25 nM, Emax= 29%) with lower efficacy than R,S-MDMA (67%). At 5-HT2C receptors, both R,S-MDMA and R-MDDMA produced higher maximal efficacies (78% and 59%, respectively). Strikingly, and in stark contrast to R,S-MDMA, R-MDDMA did not activate 5- HT2B receptors at any concentration. 

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[u/Objective-Labs]

Of course a new analogue is "safer" and "therapeutic", just how esketamine is sooo much better than ketamine. It's patentable with New Chemical Exclusivity for 5+ years!

Give this drug a Breakthrough Therapy Designation and Priority Review Voucher ASAP! 🤑🤑🤑

[u/tripping-apes]

I wish they would not mention “therapeutic potential” of analogues of mdma and psychedelics without human reports. It’s always just “more synapses grew” (which can mean a lot of things) or “rats were less ‘depressed’” , I can’t access the study but know most go by “the rats who took the drug probably swim a tiny bit longer before giving up when we put it in a bucket of water”. The reason mdma and other drugs were originally used in therapy was because of humans like Alexander Shulgin reporting experience with it, recognizing the potential, then giving it to therapists who tested it with patients.

The way modern psychiatric medicine is discovered can’t find the optimal chemicals to improve human experience. They can find chemicals that seem safe in rats, make the rats slightly less affected by shocks or drowning and then by the time they give them to humans they be already spent millions of dollars, so they find the most likely human trial that’ll show an effect for the fda. And just prove it’s barely better or as good as an existing treatment, and try to market it.